Article

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

October 2013
Journal of Inorganic Biochemistry 132(1)

October 2013
132(1)

DOI:10.1016/j.jinorgbio.2013.10.011

Source
PubMed

Authors:

Carolina Oliveira

Universidade Federal de Uberlândia (UFU)

Pedro I. S. Maia

Universidade Federal do Triangulo Mineiro (UFTM)

Paula Carolina de Souza

University of São Paulo

Fernando R Pavan

São Paulo State University

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Through a systematic variation on the structure of a series of manganese complexes derived from 2-acetylpyridine-N(4)-R-thiosemicarbazones (Hatc-R), structural features have been investigated with the aim of obtaining complexes with potent anti-Mycobacterium tuberculosis activity. The analytical methods used for characterization included FTIR, EPR, UV-visible, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. Density functional theory (DFT) calculations were performed in order to evaluate the contribution of the thiosemicarbazonate ligands on the charge distribution of the complexes by changing the peripheral groups as well as to verify the Mn-donor atoms bond dissociation predisposition. The results obtained are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral complexes of the type [Mn(atc-R)2], paramagnetic in the extension of 5 unpaired electrons, whose EPR spectra are consistent for manganese(II). The electrochemical analyses show two nearly reversible processes, which are influenced by the peripheral substituent groups at the N4 position of the atc-R(1-) ligands. The minimal inhibitory concentration (MIC) of these compounds against M. tuberculosis as well as their in vitro cytotoxicity on VERO and J774A.1 cells (IC50) was determined in order to find their selectivity index (SI) (SI=IC50/MIC). The results evidenced that the compounds described here can be considered as promising anti-M. tuberculosis agents, with SI values comparable or better than some commercial drugs available for the tuberculosis treatment.

Copper(II) complexes based on thiosemicarbazone ligand: Preparation, crystal structure, Hirshfeld surface, energy framework, antiMycobacterium activity, in silico and molecular docking studies

Article

Jul 2021
J INORG BIOCHEM

Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(μ-atc-Me)}2μ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 μM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(μ-atc-Me)}2μ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (−11.11 and − 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.

Thiazole, triazole, thio- and semicarbazone derivatives - Promising moieties for drug development for the treatment of tuberculosis

Article

Full-text available

Jun 2021

Thiazole, triazole, thio and semicarbazones are privileged motifs that act as pharmacophores in bioactive compounds for various diseases, such as Tuberculosis (TB). Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis and was responsible for 4,000 deaths a day in 2019 worldwide. The resistance and the gap of new drugs is the main cause of the slow drop in TB infections. In this review article, we analyse recent contributions of thiazole, triazole, thio and semicarbazone scaffolds to anti-TB drugs. Beyond these recent trends, we demonstrate the potential of the thiazole, triazole, thio and semicarbazone approach in the medicinal chemistry field of anti-M. tuberculosis drug discovery.

Recent Advances in Drug Discovery Against Mycobacterium tuberculosis: Metal-based Complexes

Article

Jan 2021
EUR J MED CHEM

Metal-based drugs are privileged motifs that act as primary pharmacophores in bioactive compounds for various diseases, including tuberculosis (TB). This potentially life-threatening and extremely contagious infectious disease is caused by Mycobacterium tuberculosis (Mtb). In 2018, TB infected about 10 million people and caused 1.2 million deaths worldwide. A large number of ligands are promising scaffolds in drug design, including heterocyclic, phosphines, schiff bases, thio and semicarbazones, aliphatic amines, cyclopalladated, cyanometallates and miscellaneous. Moreover, several metal-based complexes have been studied for the treatment of numerous illnesses, including infectious diseases. To contribute to drug design, we identified the metal-based organometallic complexes against Mtb. Thus, in this review article, we analysed the recent contributions of metal-based scaffolds for design of new anti-Mtb drugs in the last decade (2011 – 2020). Besides, metal-based approaches will be presented in order to find out new antitubercular agents.

Synthesis, Spectroscopic Characterization, Structural Studies, and In Vitro Antitumor Activities of Pyridine-3-carbaldehyde Thiosemicarbazone Derivatives

Article

Full-text available

Sep 2020

Eight new thiosemicarbazone derivatives, 6-(1-trifluoroethoxy)pyridine-3-carbaldehyde thiosemicarbazone (1), 6-(4′-fluorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (2), 5-chloro-pyridine-3-carbaldehyde thiosemicarbazone (3), 2-chloro-5-bromo-pyridine-3-carbaldehyde thiosemicarbazone (4), 6-(3′,4′-dimethoxyphenyl)pyridine-3-carbaldehyde thiosemicarbazone (5), 2-chloro-5-fluor-pyridine-3-carbaldehyde thiosemicarbazone, (6), 5-iodo-pyridine-3-carbaldehyde thiosemicarbazone (7), and 6-(3′,5′-dichlorophenyl)pyridine-3-carbaldehyde thiosemicarbazone (8) were synthesized, from the reaction of the corresponding pyridine-3-carbaldehyde with thiosemicarbazide. The synthesized compounds were characterized by ESI-Mass, UV-Vis, IR, and NMR (¹H, ¹³C, ¹⁹F) spectroscopic techniques. Molar mass values and spectroscopic data are consistent with the proposed structural formulas. The molecular structure of 7 has been also confirmed by single crystal X-ray diffraction. In the solid state 7 exists in the E conformation about the N2-N3 bond; 7 also presents the E conformation in solution, as evidenced by ¹H NMR spectroscopy. The in vitro antitumor activity of the synthesized compounds was studied on six human tumor cell lines: H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma). Furthermore, toxicity studies in 3T3 normal cells were carried out for the prepared compounds. The results were expressed as IC50 and the selectivity index (SI) was calculated. Biological studies revealed that 1 (IC50 = 3.36 to 21.35 μM) displayed the highest antiproliferative activity, as compared to the other tested thiosemicarbazones (IC50 = 40.00 to >582.26 μM) against different types of human tumor cell lines. 1 was found to be about twice as cytotoxic (SI = 1.82) than 5-fluorouracile (5-FU) against the M14 cell line, indicating its efficiency in inhibiting the cell growth even at low concentrations. A slightly less efficient activity was shown by 1 towards the HuTu80 and MCF7 tumor cell lines, as compared to that of 5-FU. Therefore, 1 can be considered as a promising candidate to be used as a pharmacological agent, since it presents significant activity and was found to be more innocuous than the 5-FU anticancer drug against the 3T3 mouse embryo fibroblast cells. 1. Introduction For several years, thiosemicarbazones with general formula R¹R²CH=N-NH-(C=S)-NH2 have been attracting the attention of researchers, not only because of their multifunctional coordination modes to transition metal ions [1, 2], but also because of their wide range of biological properties including antibacterial [3–6], antifungal [7], antimicobacterium tuberculosis [8, 9], and antitumoral [10–14] activity. Thiosemicarbazones usually react as chelating ligands with metal ions by bonding through the thiocarbonyl sulfur and the azomethine nitrogen atoms [15–17]. In addition to this, thiosemicarbazones and the corresponding coordination compounds have been extensively investigated for their antriproliferative activity against different human tumor cell lines. It has been shown that the mechanism of antitumoral action of α-(N)-heterocyclic thiosemicarbazones is due to its ability to inhibit the enzyme ribonucleotide diphosphate reductase, which catalyzes the conversion of ribonucleotides into deoxyribonucleotides during the DNA syntheses [18, 19]. A variety of heterocyclic thiosemicarbazones also proved to be cytotoxic against several tumor cell lines. Thus, cytotoxic studies with pyridine thiosemicarbazone derivatives: pyridine-2-carbaldehyde thiosemicarbazone, 2-acetylpyridine- 4-cyclohexyl thiosemicarbazone, and 2-formylpyridin-4-N-ethyl-thiosemicarbazone, revealed that these compounds possess higher antiproliferative activity in vitro (IC50 =< 0.55 to 4.88 μM) against MCF-7 (human breast cancer cell line), as compared to cisplatin (IC50 = 8.0 μM) [20–22]. In previous articles, we have reported the cytotoxic activity of compounds derived from benzaldehyde, naphthaldehyde, and furan-2-carbaldehyde thiosemicarbazones against different human tumor cell lines [23–25]. In vitro antitumor studies, against the chronic myelogenous leukemia (K562) and amelanotic melanoma (M-14) cell lines, revealed that compounds 2-hydroxynaphthaldehyde thiosemicarbazone (IC50 = 0.30 and 7.30 μΜ, respectively) and 4-phenyl-1-(2′-hydroxynaphthaldehyde) thiosemicarbazone (IC50 = 0.60 and 6.40 μΜ, respectively) were more cytotoxic than the corresponding naphthaldehyde thiosemicarbazone compounds (IC50 = 15.00 and 6.4 μM, respectively) and 4-phenyl-1-naphthaldehyde thiosemicarbazone (IC50 = 24.70 and >250 μΜ, respectively) [26]. In addition, in this research compound 2-hydroxynaphthaldehyde thiosemicarbazone was found to be about four times more cytotoxic than the reference drug cisplatin against the K562 cell line. As a part of our efforts towards the synthesis and structural characterization of new materials containing biorelevant pyridinyl thiosemicarbazones and the understanding of their cytotoxic activity against different human tumor cell lines, the present work describes the synthesis and spectral characterization of eight new pyridine-3-carbaldehyde thiosemicarbazone derivatives. Compounds 1–8 were tested for their in vitro antiproliferative activity against six human tumor cell lines: H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma). 2. Materials and Methods 2.1. Chemicals and Instrumentation All reagents and solvents were purchased from Sigma-Aldrich of analytical grade and were used without further purification. The tested human tumor cell lines were H460 (lung large cell carcinoma), HuTu80 (duodenum adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), M-14 (amelanotic melanoma), and HT-29 (colon adenocarcinoma), while the tested non-tumor cell line consisted of BALB/3T3 mouse embryonic fibroblast cells. Both the human tumor cell lines and the non-tumor cells were obtained from the American Type Culture Collection or from the National Cancer Institute. Cytotoxicity screening was performed using the sulforhodamine B (SRB) colorimetric assay [27]. Melting points were determined on a Büchi melting point B-545 apparatus. Elemental analyses were determined on an Elementar Vario EL analyzer. ESI-MS spectra were recorded on a Waters-Quattro Premier XE™ tandem quadrupole mass spectrometer and MicrOTOF Bruker Daltonics mass spectrometer, using methanol as the sample dissolution medium. The Infrared (IR) spectra were recorded using a Nicolet iS10 Fourier Transform Infrared (FT-IR) spectrometer equipped with an attenuated total reflectance accessory using a diamond crystal. The measurements were obtained in absorbance mode, recorded for 32 scans at a resolution of 4 cm⁻¹. All the measurements were carried out with an automatic baseline correction. The UV-VIS spectra were recorded on a Thermo Scientific Evolution 201 spectrophotometer. The ¹H (300 MHz or 400 MHz), ¹³C (75.5 MHz or 100 MHz), and ¹⁹F (376 MHz) NMR spectra were obtained on a Varian Mercury Plus 300 or Varian Mercury Plus 400 spectrometer at 299 K, using DMSO-d6 as solvent. The chemical shifts (δ) in ppm were referenced relative to residual DMSO (2.50 ppm, ¹H; 39.52 ppm, ¹³C{¹H}; ¹⁹F via IUPAC Ξ-scale with respect to the ¹H reference). The splitting of proton and carbon resonances in the reported ¹H and ¹³C NMR spectra is defined as s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. 2.2. Experimental Procedures 2.2.1. Synthesis of the Pyridine-3-carbaldehyde Thiosemicarbazone Derivatives 1–8 General Method. The pyridine-2-carbaldehyde derivative (2 mmol) in 70 mL of methanol was added dropwise to a solution of the thiosemicarbazide (0.27 g, 3 mmol) in 50 mL of methanol during 30 minutes. The mixture was refluxed for 3 h under constant stirring. Then, this liquid was stirred for 24 h at room temperature. The final mixture was filtered and the filtrate was concentrated to half the volume under reduced pressure. After a slow evaporation of the concentrate at room temperature, a solid product was obtained. It was filtered, washed several times with cold ethanol and dried in vacuo. Recrystallization of the solids was performed from hot acetone. 6-(1-Trifluoroethoxy)pyridine-3-carbaldehyde Thiosemicarbazone (1). Colorless solid. Yield 68%, m.p. 210–212°C. Anal. Cal. for C9H9ON4SF3 (278.25 g/mol): C, 38.85; H, 3.26; N, 20.14. Found: C, 38.92; H, 2.51; N, 20.75. ESI-MS: m/z 279.05 [M + H]⁺, 301.04 [M + Na]⁺. UV-VIS [DMSO, λmáx.(nm)] 317. IR (KBr): ν = 3451, 3294 (NH2), 3154 (NHCS), 1610 (CH=N), 1536 (C=N), 1059 (N-N), 865 (C=S) cm⁻¹. ¹H-NMR (300 MHz, d6-DMSO, ppm): δ 5.02 (q, 2H, OCH2CF3, J = 9.1 Hz), 8.20 and 8.08 (s, 2H, NH2), 8.46 (d, 1H: H², Py, J = 2.3 Hz), 8.41 (dd, 1H: H⁴, Py, J = 8.6, 2.3 Hz), 7.03 (d, 1H: H⁵, Py, J = 8.6 Hz), 8.03 (s, 1H, CH=N), 11.49 (s, =N-NH). ¹³C-NMR (75 MHz, d6-DMSO): δ 61.59 (q, OCH2CF3, J = 34.6 Hz), 124.04 (q, CF3, J = 277.6 Hz); 161.87, 146.81, 137.64, 125.88, 111.14 (Py); 138.80 (HC=N); 178.04 (C=S). ¹⁹F{¹H}-NMR (376 MHz, d6-DMSO): −72.85 (CF3). 6-(4-Fluorophenyl)pyridine-3-carbaldehyde Thiosemicarbazone (2 ). Colorless solid. Yield 65%, m.p. 241–243°C. Anal. Cal. for C13H11N4SF (274.32 g/mol): C, 56.92; H, 4.04; N, 20.42. Found: C, 56.94; H, 3.14; N, 20.79. ESI-MS: m/z 275.08 [M + H]⁺. UV-VIS [DMSO, λmáx.(nm)] 248, 323. IR (KBr): ν = 3422, 3273 (NH2), 3078 (NHCS), 1633 (CH=N), 1525 (C=N), 1093 (N-N), 833 (C=S) cm⁻¹. ¹H-NMR (400 MHz, −d6-DMSO, ppm): δ 7.86 (t, 2H: H2′, H6′, 4-F-Ph, J = 8.9, 5.4 Hz), 7.34 (t, 2H: H3′, H5′, 4-F-Ph, J = 8.9 Hz), 8.33 and 8.28 (s, 2H, NH2), 8.57 (t, 1H: H⁴, Py, J = 2.1 Hz), 8.85 (dd, 1H: H⁵, Py, J = 4.9, 2.1 Hz), 8.14 (s, 1H, CH=N), 11.64 (s, 1H, =N-NH). ¹³C-NMR (100 MHz, d6-DMSO, ppm): δ 162.41 (d, F-C4′, J = 245.5 Hz), 133.02 (d, J = 3.3 Hz), 129.27 (d, J = 8.4 Hz), 115.91 (d, J = 21.5 Hz) (4-F-Ph); 148.28, 147.86, 134.43, 131.05, 130.31 (Py); 138.98 (HC=N); 178.28 (C=S). ¹⁹F{¹H}-NMR (376 MHz, d6-DMSO): ‒114.54 (F-Ph). 5-Chloro-pyridine-3-carbaldehyde Thiosemicarbazone (3). Colorless solid. Yield 56%. m.p. 240–241°C. Anal. Cal. for C7H7N4SCl (214.68 g/mol): C, 39.16; H, 3.29; N, 26.10. Found: C, 39.09; H, 2.50; N, 26.66. ESI-MS: m/z 215.02 [M + H]⁺, 236.99 [M + Na]⁺. UV-VIS [DMSO, λmáx.(nm)] 324. IR (KBr): ν = 3324 (NH2), 3120 (NHCS), 1629 (CH=N), 1525 (C=N), 1096 (N-N), 843 (C=S) cm⁻¹. ¹H-NMR (300 MHz, d6-DMSO, ppm): δ 8.04 (s, 1H: H⁴, Py), 8.79 (s, 1H: H⁶, Py), 8.33 (s, 2H, NH2), 8.57 (s, 1H, CH=N), 11.66 (s, 1H, =N-NH). ¹³C-NMR (75 MHz, d6-DMSO, ppm): δ 149.00, 147.77, 133.09, 132.42, 132.04, (Py); 137.79 (HC=N); 178.85 (C=S). (5) 2-Chloro-5-bromo-pyridine-3-carbaldehyde Thiosemicarbazone (4). Yellow solid. Yield 70%. m.p. 135–137°C. Anal. Cal. for C7H6N4SBrCl (293.57 g/mol): C, 28.64; H, 2.06; N, 19.08. Found: C, 28.75; H, 1.82; N, 19.31. ESI-MS: m/z 292.93, 294.93 [M + H]⁺. UV-VIS [DMSO, λmáx.(nm)] 335. IR (KBr): ν = 3446, 3238 (NH2), 3146 (NHCS), 1602 (CH=N), 1536 (C=N), 1061 (N-N), 837 (C=S) cm⁻¹. ¹H-NMR (300 MHz, d6-DMSO, ppm): δ 9.02 (d, 1H⁴, Py, J = 3.0 Hz), 8.53 (d, 1H⁶, Py, J = 3.0 Hz), 8.45 (s, 2H, NH2), 8.28 (s, 1H, CH=N), 11.77 (s, 1H, =N-NH). ¹³C-NMR (75 MHz, d6-DMSO, ppm): δ 150.87, 148.22, 135.73, 130.78, 120.24 (Py); 138.24 (HC=N); 178.96, 171.65 (C=S). 6-(3,4-Dimethoxyphenyl)pyridine-3-carbaldehyde Thiosemicarbazone (5). Yellow solid. Yield 70%, m.p. 219–221°C. Anal. Cal. for C15H16O2N4S (316.38 g/mol): C, 56.94; H, 5.10; N, 17.71. Found: C, 56.81; H, 4.80; N, 17.54. ESI-MS: m/z 317.11 [M + H]⁺. UV-VIS [DMSO, λmáx.(nm)] 351. IR (KBr): ν = 3375, 3269 (NH2), 3116 (NHCS), 1587 (CH=N), 1531 (C=N), 1018 (N-N), 832 (C=S) cm⁻¹. ¹H-NMR (300 MHz, d6-DMSO, ppm): δ 3.81, 3.86 (s, 3H, CH3O-Ph), 7.98 (d, 1H: H2´, Ph, J = 9.0 Hz), 7.06 (d, 1H: H5´, Ph, J = 9.0 Hz), 7.74 (s, 1H: H6′, Ph); 8.15 and 8.28 (s, 2H, NH2); 8.90 (s, 1H: H², Py), 7.72 (d, 1H: H⁴, Py, J = 9.0 Hz), 8.34 (d, 1H: H⁵, Py, J = 12.0 Hz); 8.09 (s, 1H, CH=N), 11.58 (s, 1H, =N-NH). ¹³C-NMR (75 MHz, d6-DMSO, ppm): δ 149.25, 139.71, 131.17, 119.81, 112.16, 110.29 (Ph); 156.81, 150.55, 134.93, 128.61, 119.97 (Py); 149.40 (HC=N); 178.54 (C=S). 2-Chloro-5-fluor-pyridine-3-carbaldehyde Thiosemicarbazone (6). Colorless solid. Yield 82%. m.p. 139–140°C. Anal. Cal. for C7H6N4SFCl (232.67 g/mol): C, 36.13; H, 2.60; N, 24.08. Found: C, 36.15; H, 2.23; N, 24.44. ESI-MS: m/z 230.91 [M − H]⁻. UV-VIS [DMSO, λmáx.(nm)] 250, 334. IR (KBr): ν = 3457, 3290 (NH2), 3158 (NHCS), 1605 (CH=N), 1525 (C=N), 1067 (N-N), 840 (C=S) cm⁻¹. ¹H-NMR (400 MHz, d6-DMSO, ppm): δ 8.75 (dd, 1H: H⁴, Py, J = 9.5, 3.0 Hz), 8.45 (d, 1H: H⁶, Py, J = 3.0 Hz); 8.43 and 8.40 (s, 2H, NH2); 8.30 (s, 1H, CH=N), 11.79 (s, 1H, =N-NH). ¹³C-NMR (100 MHz, d6-DMSO, ppm): δ 158.82 (d, J = 253.4 Hz), 143.84 (d, J = 1.8 Hz), 138.27 (d, J = 26.8 Hz), 130.37 (d, J = 5.3 Hz), 122.57 (d, J = 22.2 Hz) (Py); 135.48 (d, HC=N, J = 2.0 Hz); 178.98 (C=S). ¹⁹F{¹H}-NMR (376 MHz, d6-DMSO): −129.36 (F-Py). 5-Iodo-pyridine-3-carbaldehyde Thiosemicarbazone (7). Colorless solid. Yield 69%. m.p. 242–244°C. MW: C7H7N4SI (306.13 g/mol), ESI-MS: m/z 305.00 [M − H]⁻. UV-VIS [DMSO, λmáx.(nm)] 267, 325. IR (KBr): ν = 3370, 3225 (NH2), 3147 (NHCS), 1683 (CH=N), 1593 (C=N), 1015 (N-N), 867 (C=S) cm⁻¹. ¹H-NMR (400 MHz, d6-DMSO, ppm): δ 8.79, (d, 1H, Py, J = 1.7 Hz), 8.75–8.76 (m, 2H, Py); 8.27 (s, 2H, NH2); 7.97 (s, 1H, CH=N); 11.62 (s, 1 H, =N-NH). ¹³C-NMR (100 MHz, d6-DMSO, ppm): δ 155.75, 147.76, 141.25, 132.44, 94.95 (Py); 138.0 (HC=N); 178. 48 (C=S). 6-(3,5-Dichlorophenyl)pyridine-3-carbaldehyde Thiosemicarbazone (8). Colorless solid. Yield 90%. m.p. 223–225°C. MW: C13H10N4SCl2 (325.22 g/mol), ESI-MS: m/z 324.91 [M − H]⁻. UV-VIS [DMSO, λmáx.(nm)] 340. IR (KBr): ν = 3356, 3256 (NH2), 3160 (NHCS), 1600 (CH=N), 1532 (C=N), 1105 (N-N), 804 (C=S) cm⁻¹. ¹H-NMR (400 MHz, d6-DMSO, ppm): δ 8.43 (d, 2H: H2′, H5′, Ph, J = 6.0 Hz), 7.68 (s, 1H: H4′, Ph); 8.98 (s, 1H: H², Py), 8.11 (s, 1H: H⁴, Py, J = 6.0 Hz), 8.14 (d, 1H: H⁵, Py, J = 6.0 Hz); 8.31 and 8.22 (s, 2H, NH2); 8.17 (s, 1H, CH=N), 11.64 (s, 1H, =N-NH). ¹³C-NMR (100 MHz, d6-DMSO, ppm): δ 139.07, 135.22, 125.58 (Ph); 153.65, 149.46, 130.65, 129.04, 121.28 (Py); 141.91 (HC=N); 178.70 (C=S). 2.2.2. Crystal Structure Determination Data were collected at 180 K using a STOE StadiVari diffractometer equipped with a copper X-ray microsource (Cu Kα radiation) and a Dectris Pilatus 300 K detector. All data were corrected for Lorentz and polarization effects; absorption effects were corrected based on numerical absorption corrections. In addition, a scaling correction was performed using Stoe X-Area software [28]. The structure of 7 was solved by direct methods (ShelxS) and refined using the full-matrix least-squares method against F² (ShelxL) [29]. Diagrams of the molecular structure showing thermal ellipsoids with 50% probability were generated using Diamond3 software [30]. 2.2.3. Biological Activity Cell Culture. BALB/3T3 cells were maintained in Dulbecco´s modified Eagle´s medium (DMEM) supplemented with 10% calf serum and 50 μg/mL gentamycin. H460, HuTu80, and DU145 were maintained in minimal essential medium (MEM) supplemented with 10% fetal bovine serum and 50 μg/mL gentamycin. MCF-7 and HT-29 were maintained in RPMI 1640 supplemented with 7.5% fetal bovine serum and 50 μg/mL gentamycin. Cells were grown at 37°C in a 5% CO2 humidified environment. Assessment of Cytotoxicity. In vitro cytotoxic activity of the prepared compounds was tested using the sulforhodamine B (SRB) assay [27]. Briefly, cells were seeded onto 96-well plates at a density of 3000–5000 cells per well and incubated at 37°C, 5% CO2, 95%, air and 95% relative humidity, with their corresponding growth medium for 24 h to allow for cell attachment. Solutions of the pyridine-3-carbaldehyde thiosemicarbazone derivatives in DMSO at different concentrations (1.95, 7.81, 31.25, and 125 μg/mL) and solutions of 5-fluorouracyl in DMSO at different concentrations (0.061, 0.244, 0.977, and 3.91 μg/mL) were added to the different cell lines and incubated for 48 h at 37°C in 5% CO2 humidified atmosphere. After 48 h, cells were treated with trichloroacetic acid (TCA), washed, dried, and stained with a solution of 0.4% sulforhodamine B in 1% acetic acid for 20 minutes. Excess stain was washed out four times with 1% acetic acid. After complete drying, the bound dye was solubilized with 10 mM Tris buffer (pH 10.5) and color intensity was measured on an automated plate reader at a wavelength of 510 nm. The IC50 value was defined as the concentration of test sample resulting in a 50% reduction of absorbance as compared with untreated controls, i.e., 50% reduction in the growth of the cells, and was determined by linear regression analysis. 3. Results and Discussion 3.1. Synthesis and Characterization Pyridine-3-carbaldehyde thiosemicarbazone derivatives 1–8 were prepared by condensing the thiosemicarbazide with a wide range of substituted pyridine 3-carbaldehydes, according to a literature procedure [24, 25], as shown in Scheme 1.

Fragmentation Study, Dual Anti-Bactericidal and Anti-Viral Effects and Molecular Docking of Cobalt(III) Complexes

Article

Full-text available

Nov 2020
INT J MOL SCI

Considering our previous findings on the remarkable activity exhibited by cobalt(III) with 2-acetylpyridine-N(4)-R-thiosemicarbazone (Hatc-R) compounds against Mycobacterium tuberculosis, the present study aimed to explored new structure features of the complexes of the type [Co(atc–R)2]Cl, where R = methyl (Me, 1) or phenyl (Ph, 2) (13C NMR, high-resolution mass spectrometry, LC–MS/MS, fragmentation study) together with its antibacterial and antiviral biological activities. The minimal inhibitory and minimal bactericidal concentrations (MIC and MBC) were determined, as well as the antiviral potential of the complexes on chikungunya virus (CHIKV) infection in vitro and cell viability. [Co(atc-Ph)2]Cl revealed promising MIC and MBC values which ranged from 0.39 to 0.78 µg/mL in two strains tested and presented high potential against CHIKV by reducing viral replication by up to 80%. The results showed that the biological activity is strongly influenced by the peripheral substituent groups at the N(4) position of the atc-R1− ligands. In addition, molecular docking analysis was performed. The relative binding energy of the docked compound with five bacteria strains was found in the range of −3.45 and −9.55 kcal/mol. Thus, this work highlights the good potential of cobalt(III) complexes and provide support for future studies on this molecule aiming at its antibacterial and antiviral therapeutic application.

Preparation, structural characterization, voltammetry and Hirshfeld surface analysis of homoleptic iron(III) thiosemicarbazone complexes

Article

Full-text available

Oct 2020
TRANSIT METAL CHEM

Reactions of FeSO4 precursor with thiosemicarbazones Hatc-R, where R is ethyl (Et) or phenyl (Ph), led to the formation of homoleptic iron(III) complexes of the type [Fe(atc-R)2]HSO4. The characterization of the compounds was performed by spectroscopy techniques, such as FTIR, UV–Vis, besides elemental analysis, conductometry, voltammetry and magnetic susceptibility measurement. The crystalline structure of [Fe(atc-Ph)2]HSO4·H2O was determined by single-crystal X-ray diffraction and revealed the oxidation of the Fe(II) centre to Fe(III) upon complexation of the monoanionic N,N,S-tridentate thiosemicarbazonate ligands. The magnetic susceptibility results showed the paramagnetic property of the iron(III) complexes in the extension of 1 unpaired electron. The electrochemical analyses showed a nearly reversible process of the iron complex, which is slightly influenced by the peripheral substituent groups at the N(4) position of the atc-R1− ligands. Hirshfeld surface analysis revealed that the supramolecular structure of [Fe(atc-Ph)2]HSO4·H2O is stabilized mainly by H···H, C···H/H···C and O···H/H···O interactions.

Unprecedented in Vitro Antitubercular Activitiy of Manganese(II) Complexes Containing 1,10-Phenanthroline and Dicarboxylate Ligands: Increased Activity, Superior Selectivity, and Lower Toxicity in Comparison to Their Copper(II) Analogs

Article

Full-text available

Jun 2018

Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), {[Mn(phen)2(H2O)2]}2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analogue of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

Article

Oct 2017
CURR MED CHEM

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

Novel Zinc(II) Complexes [Zn(atc-Et)2] and [Zn(atc-Ph)2]: In Vitro and in Vivo Antiproliferative Studies

Article

Full-text available

May 2016
INT J MOL SCI

Cisplatin and its derivatives are the main metallodrugs used in cancer therapy. However, low selectivity, toxicity and drug resistance are associated with their use. The zinc(II) (Zn(II)) thiosemicarbazone complexes [Zn(atc-Et)₂] (1) and [Zn(atc-Ph)₂] (2) (atc-R: monovalent anion of 2-acetylpyridine N4-R-thiosemicarbazone) were synthesized and fully characterized in the solid state and in solution via elemental analysis, Fourier transform infrared (FTIR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (¹H NMR) spectroscopy, conductometry and single-crystal X-ray diffraction. The cytotoxicity of these complexes was evaluated in the HepG2, HeLa, MDA-MB-231, K-562, DU 145 and MRC-5 cancer cell lines. The strongest antiproliferative results were observed in MDA-MB-231 and HepG2 cells, in which these complexes displayed significant selective toxicity (3.1 and 3.6, respectively) compared with their effects on normal MRC-5 cells. In vivo studies were performed using an alternative model (Artemia salina L.) to assure the safety of these complexes, and the results were confirmed using a conventional model (BALB/c mice). Finally, tests of oral bioavailability showed maximum plasma concentrations of 3029.50 µg/L and 1191.95 µg/L for complexes 1 and 2, respectively. According to all obtained results, both compounds could be considered as prospective antiproliferative agents that warrant further research.

Drug Discovery for TB: Frontiers and Perspectives

Chapter

Full-text available

Jul 2014

This ebook series brings updated reviews to readers interested in advances in the development of anti-infective drug design and discovery. The scope of the ebook series covers a range of topics including rational drug design and drug discovery, medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. Frontiers in Anti-Infective Drug Discovery is a valuable resource for pharmaceutical scientists and post-graduate students seeking updated and critically important information for developing clinical trials and devising research plans in this field. The third volume of this series features 6 chapters that cover a variety of topics including: - Drug Discovery for TB - Therapeutic Limitations due to Antibiotic Drug Resistance - Applications for Virus Vaccine Vectors in Infectious Disease Research - NewCastle Disease Virus - Anti-Infective Therapy Against Leishmaniasis - Anti-Viral Activity of Proanthocyanidins - See more at: http://www.eurekaselect.com/node/122731/frontiers-in-anti-infective-drug-discovery-#sthash.98q8Zzhy.dpuf

Recent developments on the potential biological applications of transition metal complexes of thiosemicarbazone derivatives

Article

Sep 2023
POLYHEDRON

The Synthesis of a Bis(thiosemicarbazone) Macrocyclic Ligand and the Mn(II), Co(II), Zn(II) and 68Ga(III) Complexes

Article

Full-text available

Jun 2021
MOLECULES

A 1,4,7,10-tetraazacyclododecane (cyclen) variant bearing two thiosemicarbazone pendant groups has been prepared. The ligand forms complexes with Mn2+, Co2+ and Zn2+. X-ray crystallography of the Mn2+, Co2+ and Zn2+ complexes showed that the ligand provides a six-coordinate environment for the metal ions. The Mn2+ and Zn2+ complexes exist in the solid state as racemic mixtures of the Δ(δ,δ,δ,δ)/Λ(λ,λ,λ,λ) and Δ(λ,λ,λ,λ)/Λ(δ,δ,δ,δ) diastereomers, and the Co2+ complex exists as the Δ(δ,δ,δ,δ)/Λ(λ,λ,λ,λ) and Δ(λ,λ,λ,δ)/Λ(δ,δ,δ,λ) diastereomers. Density functional theory calculations indicated that the relative energies of the diastereomers are within 10 kJ mol−1. Magnetic susceptibility of the complexes indicated that both the Mn2+ and Co2+ ions are high spin. The ligand was radiolabelled with gallium-68, in the interest of developing new positron emission tomography imaging agents, which produced a single species in high radiochemical purity (>95%) at 90 °C for 10 min.

Tuberculosis: An Inorganic Medicinal Chemistry Perspective

Article

Apr 2015
CURR MED CHEM

Tuberculosis (TB) which is caused by the resilient pathogen Mycobacterium tuberculosis (MTB) has re-emerged to become a leading public health problem in the world. The growing number of multi-drug resistant MTB strains and the more recently emerging problem with the extensively drug resistant strains of the pathogen are greatly undermining conventional anti-TB therapeutic strategies which are lengthy and expose patients to toxicity and other unwanted side effects. The search for new anti-TB drugs essentially involves either the repurposing of existing organic drugs which are now off patent and already FDA approved, the synthesis of modified analogues of existing organic drugs, with the aim of shortening and improving drug treatment for the disease, or the search for novel structures that offer the possibility of new mechanisms of action against the mycobacterium. Inorganic medicinal chemistry offers an alternative to organic drugs through opportunities for the design of therapeutics that target different biochemical pathways. The incorporation of metal ions into the molecular structure of a potential drug offers the medicinal chemist an opportunity to exploit structural diversity, have access to various oxidation states of the metal and also offer the possibility of enhancing the activity of an established organic drug through its coordination to the metal centre. In this review, we summarize what is currently known about the antitubercular capability of metal complexes, their mechanisms of action and speculate on their potential applications in the clinic.

Advances in Breast Cancer Drug Discovery: A Review of Therapeutic Strategies and Studies Involving Photosensitizers, Caged Xanthones and Thiosemicarbazones Derivatives

Article

Full-text available

Jan 2023
J BRAZIL CHEM SOC

Cancer is one of the major causes of death worldwide, and breast cancer is the most prevalent and deadly type among women. Despite the side effects and the phenomena of chemoresistance associated with the drugs involved, chemotherapy remains the main therapeutic strategy to combat and control breast cancer. Therefore, several new classes of compounds against breast cancer have been explored, in an effort to identify new drug candidates with alternative mechanisms of action. The principal results of such exploration, focusing on caged xanthones, thiosemicarbazones and photosensitizers, are presented in this review, along with the main aspects of the drug discovery process against breast cancer. More specifically, the design, structure-activity relationship investigations and anti-breast cancer properties of these three classes are described and discussed in this work.

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives

Article

Full-text available

Jun 2023

Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 μg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 μg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli

Article

Full-text available

Nov 2022

It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 μg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR–Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC–MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.

Zinc(II) complexes bearing N,N,S ligands: Synthesis, crystal structure, spectroscopic analysis, molecular docking and biological investigations about its antifungal activity

Article

Sep 2022
J INORG BIOCHEM

In the present work, the synthesis, characterization, antifungal activity, molecular docking study and in silico approach of five thiosemicarbazone derivatives and their corresponding zinc(II) complexes are described. The compounds were characterized by elemental analysis, IR, UV–Vis and NMR spectroscopic measurements, molar conductivity measurements, emission spectra, high-resolution mass spectrometry and X ray study. The antifungal activity of the free ligands and synthesized compounds was preliminarily evaluated against Candida albicans (ATCC 90028), Candida tropicalis (ATCC 13803) and Candida glabrata (ATCC 2001), by the minimum inhibitory concentration (MIC) assay. Two complexes, 4 (MIC = 3.18 to 6.37 μM) and 5 (MIC = 25.95 μM for all) showed promising results, being highly active against all strains evaluated. The X-ray analyses shown that the complex 2 crystallizes in the centrosymmetric space group P21/c of the monoclinic system and the coordination sphere around zinc(II) atom is better described as slightly distorted octahedral. The Hirshfeld surface (HS) analysis showed that non-classical H···H and C···H/H···C contacts contribute with 65.9% while the S···H and N···H (21%) and Cl···H and O···H interactions (12%) complete the HS area. The molecular docking results, performed against CYP51 enzyme (sterol 14α-demethylase) of C. albicans and C. glabrata shows that the complexes 4 (ΔG = −10.75 and − 12.90 kcal/ mol) and 5 (ΔG = −11.12 and − 14.53 kcal/ mol) showed the highest binding free energies of all compounds. The ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) in silico parameters evaluated showed promising results for all compounds.

Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach

Article

Full-text available

Dec 2021
INT J MOL SCI

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis.

Hybridization Approach to Drug Discovery Inhibiting Mycobacterium tuberculosis-An Overview

Article

Aug 2020

Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent mainly due to Mycobacterium tuberculosis (MTB). Recently, clinical prognoses have worsened due to the emergence of multi-drug resistant (MDR) and extensive-drug resistant (XDR) tuberculosis which lead to the need of new, efficient and safely drugs. Among the several strategies, polypharmacology could be considered one of the best solutions, in particular the multi-target directed ligands strategy (MTDLs), based on the synthesis of hybrid ligands acting against two targets of the pathogen. The framework strategy comprises linking, fusing and merging approaches to develop new chemical entities. With these premises, this review aims to provide an overview of recent hybridization approach, in medicinal chemistry, of the most recent and promising multitargeting antimycobacterial candidates.

Platinum(II) and Ruthenium(II) complexes in medicine: Antimycobacterial and Anti-HIV activities

Article

Mar 2020
COORDIN CHEM REV

Abstract Approximately 100 million people worldwide are affected by M. Tuberculosis (Mtb), a contagious disease which causes death in humans and is considered to be quite deadly throughout the world (about 1.5 million deaths annually). Approximately 20% of these deaths are attributed to strains that are resistant to drugs for combating TB. This situation is further exacerbated by the spread of HIV/AIDS worldwide. Consequently, it is important to identify and fully develop new therapeutic targets in the fight against Mtb. Treatment, over the past decades, has essentially shown limited efficacy and/or undesirable side effects. Due to the high mortality rate of TB and the increase in strains that are resistant to drugs, the exploration and synthesis of novel and more effective treatment regimens with less undesirable side effects is imperative. Two approaches are being considered a) chemical modification of currently used drugs with the intention of reducing the time for treatment and b) the exploration and synthesis of new and novel compounds which are more effective. In this regard, several transition metal complexes have been identified as potential chemotherapeutic agents against TB and HIV. Recently, the focus has been on the use of platinum and ruthenium complexes as alternative metal-based antimycobacterial and anti-HIV therapeutic agents. This minireview focuses on recent developments in the use of Pt and Ru complexes as novel therapeutic agents for TB and HIV.

In Silico Strategies in Tuberculosis Drug Discovery

Article

Full-text available

Feb 2020
MOLECULES

Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018. While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs. Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic. In silico strategies can be applied at multiple stages of the drug discovery paradigm to expedite the identification of novel anti-TB therapeutics. In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional biochemical methods. We will also highlight the strengths and points of improvement in in silico TB drug discovery research, as well as possible future perspectives in this field.

Activity Of (-)-Camphene Derivatives Against Mycobacterium tuberculosis In Acidic pH

Article

Nov 2019

Background For more than 60 years, the lack of new anti-tuberculosis drugs and the increase of resistant Mycobacterium tuberculosis lineages exhibit a therapeutic challenge, demanding new options for the treatment of resistant tuberculosis. Objective Herein, we determined the (i) activities of (-)-camphene and derivatives and (ii) combinatory effect with pyrazinamide (PZA) against Mycobacterium tuberculosis in acidic pH and (iii) cytotoxicity in VERO cells. Methods The activity of (-)-camphene and 15 derivatives were determined in M. tuberculosis H37Rv in culture medium at pH 6.0 by Resazurin Microtiter Assay Plate (REMA). The combinatory study of three (-)-camphene derivatives with PZA was carried out in seven multidrug-resistant (MDR) clinical isolates by REMA and Checkerboard, respectively. The assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide in VERO cells was used to determine the derivatives cytotoxicity. Results Four (-)-Camphene derivatives, (4), (5a) (5d) and (5h), showed reduction in MIC value at pH 6.0 compared to MIC detected at pH 6.8 in M. tuberculosis H37Rv and multidrug resistant clinical isolates. Three (-)-camphene derivatives, (4), (5d) and (5h), showed synergistic effect (FICI ≤ 0.5) combined with PZA and were more selective for M. tuberculosis than VERO cell (selective index from 7.7 to 84.2). Conclusion Three (-)-camphene derivatives have shown to be promising anti-TB molecule scaffold due to the low MIC values in acidic pH against MDR M. tuberculosis clinical isolates, synergism with PZA and low cytotoxicity.

Synthesis, characterization and antibacterial susceptibility testing of manganese complexes of doxycyline with bipyridine and phenanthroline

Article

Full-text available

Jul 2019

Three manganese complexes of the antibiotic doxycyline viz.: manganese doxycyline, [MnDox 2 ]Cl 2 ‧2H 2 O (1), and manganese doxycyline with bipyridine, [MnDox 2 (bpy)]Cl 2 ‧8H 2 O (2), and phenanthroline, [MnDox 2 (phen)]Cl 2 ‧8H 2 O (3), as the ancillary ligand were synthesized and characterized by FT-IR, elemental analysis and electrospray mass spectroscopy. The three complexes show good solubility in DMF and DMSO. Data obtained from spectroscopic techniques used show that doxycycline coordinates to the central manganese atom through the oxygen of the amide group and the carbonyl oxygen atom of ring A while bipyridine/phenanthroline coordinates through the two diimine nitrogen atoms. The stoichiometry of manganese-doxycycline is 1:2 and octahedral geometry is the preferred coordination in all the complexes.

Intramolecular interactions, isomerization and vibrational frequencies of two paracetamol analogues: A spectroscopic and a computational approach

Article

Mar 2016

Synthesis and In Vitro Evaluation of New Thiosemicarbazone Derivatives as Potential Antimicrobial Agents

Article

Full-text available

Feb 2016

In an effort to develop potent antimicrobial agents, new thiosemicarbazone derivatives were synthesized via the reaction of 4-[4-(trifluoromethyl)phenyl]thiosemicarbazide with aromatic aldehydes. The compounds were evaluated for their inhibitory effects on pathogenic bacteria and yeasts using the CLSI broth microdilution method. Microplate Alamar Blue Assay was also carried out to determine the antimycobacterial activities of the compounds against Mycobacterium tuberculosis H37Rv. Among these derivatives, compounds 5 and 11 were more effective against Enterococcus faecalis (ATCC 29212) than chloramphenicol, whereas compounds 1 , 2 , and 12 and chloramphenicol showed the same level of antibacterial activity against E. faecalis . Moreover, compound 2 and chloramphenicol exhibited the same level of antibacterial activity against Staphylococcus aureus . On the other hand, the most potent anticandidal derivatives were found as compounds 2 and 5 . These derivatives and ketoconazole exhibited the same level of antifungal activity against Candida glabrata . According to the Microplate Alamar Blue Assay, the tested compounds showed weak to moderate antitubercular activity.

Cefepime, a fourth-generation cephalosporin, in complex with manganese, inhibits proteasome activity and induces the apoptosis of human breast cancer cells

Article

Jul 2015
INT J MOL MED

Cefepime (FEP), which is a member of the fourth-generation cephalosporin class, has been extensively studied as a biochemical and antimicrobial reagent in recent years. Manganese (Mn) is important in the biochemical and physiological processes of many living organisms, and it is also high expressed in some tumor tissues. In the present study, we aimed to investigate the proteasome-inhibitory and anti-proliferative properties of 8 metal complexes (FEP‑Cu, FEP-Zn, FEP-Co, FEP-Ni, FEP-Cd, FEP-Cr, FEP-Fe, FEP-Mn) in MDA-MB‑231 human breast cancer cells. The FEP-Mn complex was found to be more potent in its ability to inhibit cell proliferation and proteasome activity than the other compounds tested. Moreover, the FEP-Mn complex inhibited proteasomal chymotrypsin-like (CT-like) activity and induced the apoptosis of breast cancer cells in a dose-and time-dependent manner. Furthermore, the MCF-10A cells were much less sensitive to the FEP complexes compared with the MDA-MB-231 breast cancer cells. These results demonstrated that the FEP-Mn(II) complex has the potential to act as a proteasome inhibitor and apoptosis inducer and therefore has possible future applications in cancer chemotherapy.

19 Schiff Bases as Antimycobacterial Agents: Synthesis, Molecular Docking and a Plausible Mechanism of Action

Article

Feb 2024
Future Med Chem

Aim: To discover novel anti- Mycobacterium tuberculosis ( Mtb) drugs, 19 compounds were synthesized; their anti- Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti- Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19 compounds inhibited Mtb growth with minimum inhibitory concentrations ranging from 1 to 32 μg/ml. Compounds 1–17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti- Mtb lead compound with a novel mechanism of action.

5-Methoxyisatin N(4)-Pyrrolidinyl Thiosemicarbazone (MeOIstPyrd) Restores Mutant p53 and Inhibits the Growth of Skin Cancer Cells, In Vitro

Article

Full-text available

Aug 2023

A series of novel thiosemicarbazone derivatives containing 5-methoxy isatin were designed and synthesized with modification on N(4) position. Derivatives considering structure-activity relationship have been designed and synthesized by condensing thiosemicarbazide with 5-methoxy isatin. The synthesized compounds were characterized by elemental analysis, FT-IR spectroscopy, UV-visible spectroscopy, NMR (1H, 13C) spectroscopy, mass spectrometry, and a single-crystal study. Biological evaluation of the synthesized compounds revealed that MeOIstPyrd is the most promising compound against skin cancer cell line, A431, with an IC50 value of 0.9 μM. In addition, MeOIstPyrd also exhibited low toxicity against the normal human fibroblast and the human embryonic kidney 293 cell line, HLF-1, and HEK293, respectively. Furthermore, the mechanistic study revealed that MeOIstPyrd efficiently inhibited cell proliferation, migration, and spheroid formation by activating the mitochondrial intrinsic apoptotic pathway. MeOIstPyrd also induces DNA damage and activates p53 irrespective of the p53 status. It increases the half-life of p53 and stabilizes p53 by phosphorylating it at ser15. Moreover, MeOIstPyrd was found to bind to MDM2 in the p53 sub-pocket and, therefore, block p53-MDM2 interaction. Our result exhibited potential anticancer activity of MeOIstPyrd in the A431 cell line and its ability in restoring mutant p53, which is an interesting and promising strategy for cancer therapeutics.

The interplay between spin states, geometries and biological activity of Fe(III) and Mn(II) complexes with thiosemicarbazone

Article

Mar 2023
POLYHEDRON

Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4

Article

Full-text available

Dec 2022
J BIOL INORG CHEM

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [CoIII(L1)2]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication). Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV-nanoluciferase in the presence of the compound, showing that [CoIII(L1)2]Cl inhibited CHIKV infection with the selective index of 3.26. [CoIII(L1)2]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [CoIII(L1)2]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [CoIII(L1)2]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [CoIII(L1)2]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects.

Synthesis, Structural Characterization, X‐ray, Hirshfeld Surfaces, DFT calculations, In Silico ADME Approach and a Molecular Docking Study of a New Nickel(II) Complex

Article

Full-text available

Oct 2022

In this study, synthesis, characterization, DFT and evaluation of the theoretical antibacterial activity through molecular docking of two different Nickel(II) complexes based on 2‐acetylpyridine‐N(4)‐R‐thiosemicarbazone are described. The ligand where R=ethyl is named L¹ and its complex [NiII(L¹)2] (Complex 1) while, for the second complex, R is phenyl (L²) resulting in a novel [NiII(L²)2] complex (Complex 2). The compounds were characterized by infrared and ultraviolet spectroscopy and elemental analysis. The molecular structure of 1 was determined by single‐crystal X‐ray diffraction. The complex crystallizes in monoclinic crystal system, adopting a distorted octahedral geometry and the crystal lattice is stabilized by H⋅⋅⋅H, C⋅⋅⋅H/H⋅⋅⋅C, N⋅⋅⋅H/H⋅⋅⋅N and S⋅⋅⋅H/H⋅⋅⋅S interactions (Hirshfeld Surfaces). The results of density functional theory provided information about molecular structures, molecular frontier orbital and theorical IR and the UV‐Vis spectra of 1 and 2. The molecular docking and in silico analysis of pharmacokinetic parameters of the compounds showed promising results.

Copper(II) complexes based on 1,3,4-thiadiazolethiosemicarbazone NNS donor ligands: synthesis, molecular structure, DNA binding and in silico molecular docking approach

Article

Dec 2021

Two derivatives of 1,3,4-thiadiazolethiosemicarbazone were used to synthesize Cu(II) complexes in 1:1 (M:L) molar ratio using chloride and acetate copper salts. The formulae of the obtained complexes were confirmed to be [L¹CuCl(H2O)2]‧H2O, [L¹Cu(OAc)(H2O)2]‧0.5H2O, [L²CuCl] and [L²Cu(OAc)(H2O)2]‧0.5CH3OH; where HL¹ and HL² are p-methylphenyl and p-nitrophenyl derivatives of 1,3,4-thiadiazolethiosemicarbazone. In the copper complexes, the two ligands act as monovalent anionic tridentate NNS donors. The geometries around the Cu(II) centers were concluded to be square planar and octahedral based on thermal analysis, electronic spectra and magnetic moment values. Evaluation of the binding mode of the ligands and their copper chelates with DNA; salmon sperm type (SS-DNA), were assessed applying UV-Vis spectral titration and viscosity measurements. The binding extent and binding mode of the organic ligands and their copper chelates with DNA was evaluated from calculation of the binding constant (kb) and compared with ethidium bromide. The binding energies of the obtained compounds with DNA were calculated by performing molecular docking studies in order to recognize the drug-DNA interactions ability. Molecular docking studies of the synthesized compounds were studied and revealed their intercalative binding potential into the DNA

Characterization of oxorhenium(V) complexes with a benzyldithiocarbazate ligand: synthesis, spectroscopic and DFT analysis

Article

Jan 2022
J MOL STRUCT

Three new neutral oxorhenium(V) complexes were prepared with a 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyldithiocarbazate) ligand (H2bdtc): ReOCl(bdtc)(triphenylphosphine) [1], ReOBr(bdtc)(triphenylphosphine) [2] and ReO(bdtc)(cysteamine) [3]. These rhenium complexes were characterized based on elemental, ESI(+)-MS, IR, NMR (¹H and ³¹P), and X-ray diffraction analysis. The bdtc ligand took on different coordination arrangements for the three rhenium complexes, a planar conformation for 1 and a facial conformation for complex 3. Complexes 1 and 3 crystallize with monoclinic space groups P21/n and P21/c, respectively. The conformational stability caused by the unimolecular arrangement of the ligands was evaluated by the Density Functional Theory (DFT) calculation with the purpose of determining the balance involving the equilibrium among the possible stereoisomers in isolated phase and solvent. Moreover, frontier molecular orbitals, Natural Bond Orbital (NBO), Quantum Theory of Atoms in Molecules (QTAIM), bond order indices and molecular electrostatic potential analysis were performed to understand the electronic properties.

Development of gold(III) thiosemicarbazonate complex–loaded PLGA nanoparticles: characterization and sustained release studies

Article

Full-text available

Nov 2020
J NANOPART RES

The gold(III) complex [AuCl(L1)] has been reported as a lead candidate for Chagas’ disease (CD) treatment. However, in order to be effective, the drug must first reach the target tissue and then be delivered in therapeutic amounts. In this context, nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) have been developed to be used as delivery systems for [AuCl(L1)]. The [AuCl(L1)]-PLGA-NPs were prepared via the emulsification and solvent evaporation technique and displayed encapsulation efficiency around 90% with the size range of 275 ± 5 nm, polydispersity index (PDI) around 0.115, and a higher value of zeta potential (− 6.51 ± 0.47 mV) compared to blank NPs (without gold complex), which agree with the formation of a cationic species in solution, as indicated by computational calculations. Additionally, high-resolution images obtained by SEM showed the [AuCl(L1)]-PLGA-NPs spherical shape with average sizes close to those analyzed by the DLS technique. Stability studies for the [AuCl(L1)]-PLGA-NPs pointed out that no significant changes in relation to size and PDI occur over almost 2 months of storage at 8 °C. The release of the complex from NPs was about 10% in 24 h, followed by a slow release. By means of the Korsmeyer-Peppas model, it was possible to identify the release mechanism as being through diffusion and relaxation of the polymeric matrix. Overall, it has been shown that the PLGA-NPs are promising carriers for delivery of [AuCl(L1)] and are recommended to be investigated as formulations for parasite treatment in vivo experiments. Graphical abstract

Cytotoxic effects, microbiological analysis and inhibitory properties on carbonic anhydrase isozyme activities of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone and its Cu(II), Co(II), Zn(II) and Mn(II) complexes

Article

Full-text available

Feb 2021
RES CHEM INTERMEDIAT

Metal complexes of thiosemicarbazones have been receiving considerable attention in biological applications such as antimicrobial and anticancer therapies. In this work, Co(II), Zn(II) and Mn(II) complexes of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) were synthesized for the first time and characterized by EPR, FT-IR, NMR, UV-Vis spectroscopies, TG/DSC and elemental analysis. X-ray powder diffraction analysis was carried out for Zn(II) complex. HMAT and its Cu(II), Co(II), Zn(II) and Mn(II) complexes were tested as enzyme inhibitory agents. All compounds are effective inhibitor of cytosolic carbonic anhydrase I and II isoforms (hCA I and II) enzymes. IC 50 values of HMAT and its Cu(II), Co(II), Zn(II) and Mn(II) complexes were determined as 93.35, 324.46, 25.67, 1.06 and 22.36 μM for CA I isozyme and 99.02, 86.64, 57.76, 10.34 and 36.48 μM for CA II isozyme, respectively. The evaluation of potential cytotoxic effects of the compounds was performed against normal epithelial breast mammary gland CRL-4010, estrogen-positive low metastatic MCF-7 and triple negative highly metastatic MDA-MB-231 breast adenocarcinoma cell lines by MTT assay. The results showed that the tested metal complexes have high cytotoxic effects than their ligand molecule. In particular, the Cu(II) complex displayed preciously high cytotoxic properties different from the others. Given these facts, the Cu(II) complex could be debated as potential chemotherapeutic molecule against drug-resistant breast cancer cells. Minimum inhibitory concentrations of the compounds against the test organisms were also detected for the microbiological analysis.

Molecular events and cytotoxic effects of a novel thiosemicarbazone derivative in human leukemia and lymphoma cell lines

Article

Full-text available

Jul 2020

The present study aimed to investigate the cytotoxic effect of 38 new thiosemicarbazone derivatives on hematological neoplastic cells lines and to select the most effective compounds to investigate the main molecular mechanisms involved in cell death. Cytotoxicity screening on Daudi and Jurkat cells revealed that only compound 1b met the selection criteria; therefore, it was chosen for further investigation. Cell viability of Daudi, Jurkat, Molt-4, Namalwa, K562, and MM.1S cell lines decreased in a concentration- and time-dependent manner after 1b incubation; nevertheless the compound neither caused significant hemolysis nor reduction in peripheral blood mononuclear cell viability. Although no changes were observed on cell cycle or Ki-67 expression, 1b induced apoptotic-like cell death with mitochondrial involvement, Bax/Bcl-2 inversion, AIF release, survivin inhibition, and caspase-3 activation in both Daudi and Jurkat cells. Furthermore, the compound reduced NFκB expression in Jurkat cells. In Daudi cells, 1b also decreased CHOP, Akt, pAkt, and MAPK/ERK2 expression, thereby suggesting modulation of UPR, PI3K/Akt/mTOR, and MAPK/ERK signaling pathways. Finally, the compound was able to reduce the cell viability of samples collected from patients with different lymphoid neoplasms subtypes, showing that thiosemicarbazones derivatives could be used in the development of new drugs with anticancer activity.

PLGA-Nanoparticles loaded with a thiosemicarbazone derived palladium (II) complex as a Potential Agent to New Formulations for human ovarian carcinoma treatment

Article

Jul 2020

The complex named triphenylphosphane-chlorido(pyrenecarboxaldehyde-N(3)-cyclohexyl-thiosemicarbazonate)palladium(II), [PdCl(PPh3)(PrCh)], has been recently selected as a promising cytotoxic agent against resistant ovarian cancer cells, by inhibiting the topoisomerase IB enzyme. In order to increase the efficacy of this promising drug, in the present work the influence of the encapsulation process of PdII complex into poly(lactic-co-glycolic acid) (PLGA) polymer was studied. The PLGA nanoparticles containing the PdII complex (NPs-PLGA-PdII) were prepared by using an emulsion-solvent evaporation technique and fully characterized by using DLS and SEM. The results showed that the PLGA-NPs containing the PdII complex can be obtained successfully through an emulsion-solvent evaporation method with a high encapsulation efficiency (96 %). Furthermore, the PLGA-NPs revealed to be suitable as a controlled release carrier system for [PdCl(PPh3)(PrCh)], since in vitro tests displayed a slow and sustained release of the PdII complex. After the PdII encapsulation on the PLGA-NPs, biological studies were assayed by using the OVCAR3 cell line (human ovarian carcinoma cells). The study of cytotoxicity by resazurin assay showed that the formulation led to a significant reduction of the ovarian cell viability (80 % at 1 μM) more than the non-encapsulated complex or cisplatin. Most notably, it must be highlighted the relevant cytotoxicity of the Nano-PLGA-PdII against cisplatin resistant cell line used in this work since resistance is one of the major challenges for chemotherapy.

Novel tetranuclear Pd II and Pt II anticancer complexes derived from pyrene thiosemicarbazones

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Full-text available

Jun 2020

Cyclometallated palladium(II) and platinum(II) pyrenyl-derived thiosemicarbazone (H2PrR) complexes of the type [M4(μ-S-PrR-κ³-C,N,S)4] (M = PdII, PtII; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt4(μ-S-PrCh-κ³-C,N,S)4](CH3)2COCHCl3 contains an eight-membered ring of alternating M–S atoms. The ethyl derivatives [M4(μ-S-PrEt-κ³-C,N,S)4] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC50 values of 1.27 μM (for M = PdII) and 0.37 μM (for M = PtII), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC50 1.20 μM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.

A bioinorganic chemistry perspective on the roles of metals as drug and targets against Mycobacterium tuberculosis - a journey of opportunities

Article

Jun 2020

Medicinal inorganic chemists have provided many strategies to tackle a myriad of diseases, pushing forward the frontiers of pharmacology. As an example, the fight against tuberculosis (TB), an infectious bacterial disease, has led to the development of metal-based compounds as potential drugs. This disease remains a current health issue causing over 1.4 million of deaths per year. The emergence of multi- (MDR) and extensively-drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains along with a long dormancy process, place major challenges in developing new therapeutic compounds. Isoniazid is a front-line prodrug used against TB with appealing features for coordination chemists, which have been explored in a series of cases reported here. An isoniazid iron-based compound, called IQG-607, has caught our attention, whose in vitro and in vivo studies are advanced and thoroughly discussed, along with other metal complexes. Isoniazid is inactive against dormant Mtb, a hard to eliminate state of this bacillus, found in ¼ of the World population and directly implicated in the lengthy treatment of TB (ca. 6 months). Thus, our understanding of this phenomenon may lead to a rational design of new drugs. Along these lines, we describe how metals as targets can cross paths with metals used as selective therapeutics, where we mainly review heme-based sensors, DevS and DosT, as a key system in Mtb dormancy process and a current drug target. Overall, we report new opportunities for bioinorganic chemists to tackle this longstanding and current threat.

4-Substituted picolinohydrazonamides as a new class of potential antitubercular agents

Article

Full-text available

Jan 2020

The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4-0.8 μg/mL) was higher than that of reference drugs. Moreover, derivative 15 exhibited lower activity against other tested microorganism such as bacteria gram-positive, gram-negative or fungi. Thus, this compound is characterized by the selectivity of antimicrobial activity. Antiproliferative study conducted against human dermal fibroblasts (HDF) and mouse melanoma cell line (B16-F10) revealed low cytotoxicity of compound 15. Conducted research allowed to identify compound 15 as leading for further research.

Palladium (II) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

Article

Full-text available

Oct 2019

New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the...

Group 10 metal complexes with a tetradentate thiosemicarbazonate ligand: Synthesis, crystal structures and computational insights into the catalysis for C–C coupling via Mizoroki-Heck reaction

Article

Aug 2019
J MOL STRUCT

A series of mononuclear complexes has been synthesized by reactions of group 10 metal ions with bis(4-phenyl-3-thiosemicarbazone) (H2bPht), affording compounds of general formula [MII(bPht)] (M = Ni, Pd and Pt). Their characterization involved FTIR, UV–Vis, 1H NMR, CV, DPV and elemental analysis. Furthermore, the crystal structures of all complexes have been determined, showing that the thiosemicarbazonate ligand is coordinated as a tetradentate N,N,S,S-donor forming three five-membered chelate rings. The catalytic activity of [MII(bPht)] in Heck's C–C coupling reaction using styrene and iodobenzene to obtain stilbenes has been evaluated. It was verified that the NiII and PtII complexes present low catalytic activity, while the PdII complex showed a conversion of 99% within 24 h. Trans-stilbene was identified as the major product of the coupling reaction, up to 90%. DFT studies were also performed in order to better understand the catalytic behavior of these complexes giving support for a new route for Mizoroki-Heck reaction.

Crystal packing of a zinc(II)-azide complex with a N,N,S-tridentate thiosemicarbazone ligand: An experimental and computational study

Article

Jul 2019
J MOL STRUCT

The aim of this study was to provide a crystallographic and electronic analysis of a zinc(II)-azide complex with a N,N,S-tridentate thiosemicarbazone ligand. The characterization was performed by single-crystal X-ray diffraction, elemental analysis and FT-IR spectroscopy. This compound showed a distorted square-planar structure and its crystal structure was in the triclinic space group P1¯ with Z = 2. Based on the Hirshfeld surface analysis, the van der Waals forces, N⋅⋅⋅H hydrogen bonds and C–H⋅⋅⋅π are the main intermolecular interactions that stabilize the crystal packing assembly. In addition, the Density Functional Theory (DFT) was used to predict the electronic properties. DFT calculations estimated interaction energy of −12.6 kcal mol⁻¹ required to form the dimer structure. Nevertheless, based on a Natural Bond Orbital (NBO) analysis, two hydrogen bonds between nitrogen atoms of the azide group and the hydrogen atom of the amine one (N–H⋅⋅⋅N) are the main interactions responsible for the stabilization of the dimer structure studied. In addition, we were also able to characterize other important intermolecular interactions as the Sulfur⋅⋅⋅Sulfur and the C–H⋅⋅⋅N formed between the azide groups and the aromatic rings performed with the Quantum Theory of Atoms in Molecules (QTAIM).

Isolation, characterization and biological activity of organic extractives from Calodendrum capense (L.f.) Thunb.(Rutaceae)

Article

Full-text available

Apr 2018
J MED PLANTS RES

Photophysical and DFT Studies of Cationic Ag(I) Complexes with Thiosemicarbazides Derived from p‐Toluenesulfohydrazide

Article

Feb 2018

Reactions of p-toluenesulfohydrazide with R-isothiocyanates afford new ligands containing both the sulfonamide and thiosemicarbazide moieties (LR: R=cyclohexyl (Cy) or phenyl (Ph)). LR reacts with AgNO3 in EtOH in a 2:1 M ratio leading to formation of colourless Ag(I) complexes of general formula [Ag(LR)2]NO3. The crystal structure of a representative complex was determined by crystallographic studies and shows the Ag(I) coordinated by two thiosemicarbazide ligands in a S-monodentate coordination mode along with a significant interaction with a nitrate counter-ion in a bent geometry. Photophysical studies show that both the free ligands and complexes are essentially non-luminescent at room temperature. At 77 K and glassy media, the silver complexes exhibit a luminescence band in the visible-light region. Besides, experimental and theoretical analyses suggest the population of the triplet state of these complexes after electronic excitation at around 250 nm. Overall, it was verified that the observed emission of the Ag(I) complexes can be attributed to 3MLCT radiative decay and that the silver complex with LPh shows a higher intensity emission than the complex with LCy.

Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry

Article

Full-text available

Feb 2018

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics.

Apoptotic mechanisms of nickel(II) complex with N1-acetylacetone-N4- 4-methoxy-salicylidene-S-allyl-thiosemicarbazone on HL60 leukemia Cells

Article

Full-text available

Jan 2016

Thiosemicarbozone complexes that have a broad spectrum of biological activity are formed as a result of condensation reaction between thiosemicarbazide [H2N(C=S)-NH-NH2] and carbonyl-containing compounds. A new nickel(II) complex with N1-acetylacetone-N4-4-methoxysalicylidene- S-allyl-thiosemicarbazone ligand was synthesized and characterized. We studied the antileukemic activity of the Ni(II) thiosemicarbazone compound and assessed their potential for drug development. Specifically, the effects of this Ni(II) thiosemicarbazone compound on intracellular signal nodes and apoptotic pathways were investigated. According to our results, the Ni(II) thiosemicarbazone compound has apoptotic activity against HL60 cells. Moreover, while Ni(II) thiosemicarbazone compound significantly increased levels of p53 and cleaved caspase-3 proteins, it decreased level of Phospho-Akt1 protein in HL60 cells. The Ni(II) thiosemicarbazone compound could induce HL60 cell apoptosis through inhibiting of PI3K/Akt pathway. These results showed that Ni(II) thiosemicarbozone compound might be an antileukemic agent.

Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs

Article

May 2016

Potential of Casiope�nas� Copper Complexes and Antituberculosis Drug Combination against Mycobacterium tuberculosis

Article

Mar 2016
CHEMOTHERAPY

New compounds with antituberculosis activity and their combination with classic drugs have been evaluated to determine possible interactions and antagonism. The aim of this study was to evaluate the in vitro activity of Casiopeínas® copper-based compounds (CasIIIia, CasIIIEa, and CasIIgly) alone and combined with isoniazid (INH), rifampicin, or ethambutol (EMB) against resistant and susceptible Mycobacterium tuberculosis. Seventeen clinical M. tuberculosis isolates (5 multi-drug resistant and 2 resistant to INH and/or EMB) were subjected to determination of the minimal inhibitory concentration (MIC) by the resazurin microtiter assay and combination assessment by the resazurin drug combination microtiter assay. The Casiopeínas® alone showed a remarkable effect against resistant isolates with MIC values from 0.78 to 12.50 μg/ml. Furthermore, a synergistic effect mainly with EMB is shown for both resistant and susceptible clinical isolates. Casiopeínas® are promising candidates for future investigation into the development of antituberculosis drugs, being one of the first examples of essential metal-based drugs used in this field.

Cobalt(III) Complexes with Thiosemicarbazones as Potential anti-Mycobacterium tuberculosisAgents

Article

Full-text available

Oct 2014
J BRAZIL CHEM SOC

CoIII complexes derived from 2-acetylpyridine N(4)-R thiosemicarbazone (Hatc-R, R = alkyl, aryl) have been characterized by elemental analysis, FTIR, UV-Visible and 1 H NMR spectroscopies, cyclic voltammetry (CV), conductimetry measurements and single crystal X-ray diffractometry. The results obtained are consistent with the oxidation of the CoII center to CoIII upon coordination of the monoanionic N,N,S-tridentate thiosemicarbazone ligands, resulting in octahedral ionic complexes of the type [Co(atc-R)2]Cl. Electrochemistry studies show two reversible processes referring to the redox couples CoIII/CoII and CoII/CoI which can be modified by the inductive effects of the substituents groups at the N4 position of the ligands. Two CoIII complexes showed satisfactory activity with minimal inhibitory concentration value under 10 μmol L–1 and one presented quite low cytotoxicity against VERO and J774A.1 cells (IC50), resulting in high selectivity index (SI > 10).

Natural Population Analysis

Article

Full-text available

Jul 1985
CHEM PHYS

A method of 'natural population analysis' has been developed to calculate atomic charges and orbital populations of molecular wave functions in general atomic orbital basis sets. The natural analysis is an alternative to conventional Mulliken population analysis, and seems to exhibit improved numerical stability and to better describe the electron distribution in compounds of high ionic character, such as those containing metal atoms. An ab initio calculation is conducted of SCF-MO wave functions for compounds of type CH3X and LiX (X = F, OH, NH2, CH3, BH2, BeH, Li, H) in a variety of basis sets to illustrate the generality of the method, and to compare the natural populations with results of Mulliken analysis, density integration, and empirical measures of ionic character. Natural populations are found to give a satisfactory description of these molecules, providing a unified treatment of covalent and extreme ionic limits at modest computational cost.

Next-Generation Ion Torrent Sequencing of Drug Resistance Mutations in Mycobacterium tuberculosis Strains

Article

Full-text available

Nov 2012
J CLIN MICROBIOL

A novel protocol for full-length Mycobacterium tuberculosis gene analysis of first- and second-line drug resistance was developed using the Ion Torrent Personal Genome Machine (PGM). Five genes—rpoB (rifampin), katG (isoniazid), pncA (pyrazinamide), gyrA (ofloxacin/fluoroquinolone), and rrs (aminoglycosides)—were amplified and sequenced, and results were compared to those obtained by genotypic Hain line probe assay (LPA) and phenotypic Bactec MGIT 960 analysis using 26 geographically diverse South African clinical isolates collected between July and November 2011. Ion Torrent sequencing exhibited 100% (26/26) concordance to phenotypic resistance obtained by MGIT 960 culture and genotypic rpoB and katG results by LPA. In several rifampin-resistant isolates, Ion Torrent sequencing revealed uncommon substitutions (H526R and D516G) that did not have a defined mutation by LPA. Importantly, previously uncharacterized mutations in rpoB (V194I), rrs (G878A), and pncA (Q122Stop) genes were observed. Ion Torrent sequencing may facilitate tracking and monitoring geographically diverse multidrug-resistant and extensively drug-resistant strains and could potentially be integrated into selected regional and reference settings throughout Africa, India, and China.

Toward reliable density functional methods without adjustable parameters: The PBE0 model

Article

Full-text available

Apr 1999

We present an analysis of the performances of a parameter free density functional model (PBE0) obtained combining the so called PBE generalized gradient functional with a predefined amount of exact exchange. The results obtained for structural, thermodynamic, kinetic and spectroscopic (magnetic, infrared and electronic) properties are satisfactory and not far from those delivered by the most reliable functionals including heavy parameterization. The way in which the functional is derived and the lack of empirical parameters fitted to specific properties make the PBE0 model a widely applicable method for both quantum chemistry and condensed matter physics.

The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06 functionals and 12 other functionals

Article

Full-text available

Apr 2008

We present two new hybrid meta exchange- correlation functionals, called M06 and M06-2X. The M06 functional is parametrized including both transition metals and nonmetals, whereas the M06-2X functional is a high-nonlocality functional with double the amount of nonlocal exchange (2X), and it is parametrized only for nonmetals.The functionals, along with the previously published M06-L local functional and the M06-HF full-Hartree–Fock functionals, constitute the M06 suite of complementary functionals. We assess these four functionals by comparing their performance to that of 12 other functionals and Hartree–Fock theory for 403 energetic data in 29 diverse databases, including ten databases for thermochemistry, four databases for kinetics, eight databases for noncovalent interactions, three databases for transition metal bonding, one database for metal atom excitation energies, and three databases for molecular excitation energies. We also illustrate the performance of these 17 methods for three databases containing 40 bond lengths and for databases containing 38 vibrational frequencies and 15 vibrational zero point energies. We recommend the M06-2X functional for applications involving main-group thermochemistry, kinetics, noncovalent interactions, and electronic excitation energies to valence and Rydberg states. We recommend the M06 functional for application in organometallic and inorganometallic chemistry and for noncovalent interactions.

Palladium(II) Complexes with Thiosemicarbazones. Syntheses, Characterization and Cytotoxicity against Breast Cancer Cells and Anti-Mycobacterium tuberculosis Activity

Article

Full-text available

Dec 2009
J BRAZIL CHEM SOC

Three Pd(II) complexes were prepared from N(4)-substituted thiosemicarbazones: [Pd(aptsc)(PPh(3))](NO(3))center dot H(2)O, 1, [Pd(apmtsc)(PPh(3))](NO(3)), 2, and [Pd(apptsc)(PPh(3))](NO(3))center dot H(2)O, 3, where PPh(3) = triphenylphosphine; Haptsc = 2-acetylpyridine-thiosemicarbazone; Hapmtsc = 2-acetylpyridine-N(4)-methyl-thiosemicarbazone and Happtsc = 2-acetylpyridine-N(4)-phenyl-thiosemicarbazone. All complexes were characterized by elemental analysis, IR, UV-Vis, (1)H and (31)P(1)H NMR spectroscopies, and had their crystalline structures determined by X-ray diffractometry from single crystals. The monoanionic thiosemicarbazonate ligands act in a tridentate mode, binding to the metal through the pyridine nitrogen, the azomethine nitrogen and the sulfur atoms. The cytotoxic activity against the breast cancer cell line MDA-MB231 and the anti-Mycobacterium tuberculosis H(37)Rv ATCC 27294 activity were evaluated for the compounds. All Pd(II) complexes were highly active against the studied cell line, presenting similar values of IC(50), around 5 mu mol L(-1), while the clinically applied antitumor agent cisplatin was inactive. The compounds show remarkable anti-M. tuberculosis activities, presenting MIC values comparable or better than some commercial anti-M tuberculosis drugs.

Continuous surface charge polarizable continuum models of solvation. I. General formalism

Article

Full-text available

Mar 2010
J CHEM PHYS

Continuum solvation models are appealing because of the simplified yet accurate description they provide of the solvent effect on a solute, described either by quantum mechanical or classical methods. The polarizable continuum model (PCM) family of solvation models is among the most widely used, although their application has been hampered by discontinuities and singularities arising from the discretization of the integral equations at the solute-solvent interface. In this contribution we introduce a continuous surface charge (CSC) approach that leads to a smooth and robust formalism for the PCM models. We start from the scheme proposed over ten years ago by York and Karplus and we generalize it in various ways, including the extension to analytic second derivatives with respect to atomic positions. We propose an optimal discrete representation of the integral operators required for the determination of the apparent surface charge. We achieve a clear separation between "model" and "cavity" which, together with simple generalizations of modern integral codes, is all that is required for an extensible and efficient implementation of the PCM models. Following this approach we are now able to introduce solvent effects on energies, structures, and vibrational frequencies (analytical first and second derivatives with respect to atomic coordinates), magnetic properties (derivatives with respect of magnetic field using GIAOs), and in the calculation more complex properties like frequency-dependent Raman activities, vibrational circular dichroism, and Raman optical activity.

Cloning, expression and characterization of the catalase-peroxidase (KatG) gene from a fast-growing Mycobacterium sp. strain JC1 DSM 3803

Article

Full-text available

Nov 2009
J BIOCHEM

The gene encoding a catalase–peroxidase (KatG) was cloned from chromosomal DNA of a fast-growing Mycobacterium sp. strain JC1 DSM 3803. The nucleotide sequence of a 5.7 kb EcoRI fragment containing the katG and its flanking regions was determined. The fragment (5,706 bps) contained two complete open reading frames (ORFs) encoding putative ferric uptake regulator A (FurA) and KatG proteins. The cloned gene, katG, had an ORF of 2241 nt, encoding a protein with calculated molecular mass of 81,748 Da. The furA was located in the upstream of the katG with the same transcriptional direction and there was a 38 bp gap space between them. The deduced KatG and FurA protein sequences showed significant homologies to KatG2 and Fur2 of Mycobacterium smegmatis and clustered with other mycobacterial KatG and Fur-like proteins in phylogenetic trees, respectively. The recombinant KatG overproduced in Escherichia coli was nearly indistinguishable from the native JC1 catalase–peroxidase in enzymatic properties and also possessed the resistance to organic solvents, indicating that the cloned katG truly encodes the Mycobacterium sp. JC1 catalase–peroxidase. Difference spectroscopy revealed Mn(II) binding near the haem of the KatG. Transcript analysis of the furA–katG using RT–PCR suggests that the katG is independently transcribed from the furA.

The Role of Mn(II)-Peroxidase Activity of Mycobacterial Catalase-Peroxidase in Activation of the Antibiotic Isoniazid

Article

Full-text available

May 1997

The catalase-peroxidase of Mycobacteria smegmatis exhibits Mn(II)-peroxidase activity characterized by a low Km for Mn(II) (5 μM) and a high Km for t-butyl hydroperoxide (100 mM). This activity, monitored by the formation of Mn(III)-malate or -malonate, is inhibited by Co(II) but not by superoxide dismutase. Optical evidence for binding of Mn(II) to the resting (ferric) enzyme is found in a change in intensity of the Soret peak upon titration with Mn(II). A potential role for Mn(III) in the antimycobacterial action of the antibiotic isoniazid is suggested by the rapid reduction of Mn(III)-malonate by this drug. The stoichiometry of the reaction is consistent with two single electron transfer steps per mole of isoniazid.

Mn(III) Pyrophosphate as an Efficient Tool for Studying the Mode of Action of Isoniazid on the InhA Protein of Mycobacterium tuberculosis

Article

Full-text available

Jul 2002
ANTIMICROB AGENTS CH

The antituberculosis drug isoniazid (INH) is quickly oxidized by stoichiometric amounts of manganese(III) pyrophosphate. In the presence of nicotinamide coenzymes (NAD+, NADH, nicotinamide mononucleotide [NMN+]) and nicotinic acid adenine dinucleotide (DNAD+), INH oxidation produced the formation of INH-coenzyme adducts in addition to known biologically inactive products (isonicotinic acid, isonicotinamide, and isonicotinaldehyde). A pool of INH-NAD(H) adducts preformed in solution allowed the rapid and strong inhibition of in vitro activity of the enoyl-acyl carrier protein reductase InhA, an INH target in the biosynthetic pathway of mycolic acids: the inhibition was 90 or 60% when the adducts were formed in the presence of NAD+ or NADH, respectively. Under similar conditions, no inhibitory activity of INH-NMN(H) and INH-DNAD(H) adducts was detected. When an isolated pool of 100 nM INH-NAD(H) adducts was first incubated with InhA, the enzyme activity was inhibited by 80%; when present in excess, both NADH and decenoyl-coenzyme A are able to prevent this phenomenon. InhA inhibition by several types of INH-coenzyme adducts coexisting in solution is discussed in relation with the structure of the coenzyme, the stereochemistry of the adducts, and their existence as both open and cyclic forms. Thus, manganese(III) pyrophosphate appears to be an efficient and convenient alternative oxidant to mimic the activity of the Mycobacterium tuberculosis KatG catalase-peroxidase and will be useful for further mechanistic studies of INH activation and for structural investigations of reactive INH species in order to promote the design of new inhibitors of InhA as potential antituberculous drugs.

Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in Mycobacterium tuberculosis

Article

Full-text available

Aug 2002
ANTIMICROB AGENTS CH

A method for detecting multidrug-resistant Mycobacterium tuberculosis by using a reduction of resazurin is described. Eighty clinical isolates were evaluated against isoniazid and rifampin; results at 7 days were compared with those of the proportion method. Specificity and sensitivity were excellent. The method is simple, inexpensive, and rapid and might be used with other antituberculosis drugs.

Semiempirical Hybrid Density Functional with Perturbative Second-Order Correction

Article

Full-text available

Feb 2006

Stefan Grimme

A new hybrid density functional for general chemistry applications is proposed. It is based on a mixing of standard generalized gradient approximations (GGAs) for exchange by Becke (B) and for correlation by Lee, Yang, and Parr (LYP) with Hartree-Fock (HF) exchange and a perturbative second-order correlation part (PT2) that is obtained from the Kohn-Sham (GGA) orbitals and eigenvalues. This virtual orbital-dependent functional contains only two global parameters that describe the mixture of HF and GGA exchange (a(x)) and of the PT2 and GGA correlation (c), respectively. The parameters are obtained in a least-squares-fit procedure to the G297 set of heat of formations. Opposed to conventional hybrid functionals, the optimum a(x) is found to be quite large (53% with c=27%) which at least in part explains the success for many problematic molecular systems compared to conventional approaches. The performance of the new functional termed B2-PLYP is assessed by the G297 standard benchmark set, a second test suite of atoms, molecules, and reactions that are considered as electronically very difficult (including transition-metal compounds, weakly bonded complexes, and reaction barriers) and comparisons with other hybrid functionals of GGA and meta-GGA types. According to many realistic tests, B2-PLYP can be regarded as the best general purpose density functional for molecules (e.g., a mean absolute deviation for the two test sets of only 1.8 and 3.2 kcal/mol compared to about 3 and 5 kcal/mol, respectively, for the best other density functionals). Very importantly, also the maximum and minimum errors (outliers) are strongly reduced (by about 10-20 kcal/mol). Furthermore, very good results are obtained for transition state barriers but unlike previous attempts at such a good description, this definitely comes not at the expense of equilibrium properties. Preliminary calculations of the equilibrium bond lengths and harmonic vibrational frequencies for diatomic molecules and transition-metal complexes also show very promising results. The uniformity with which B2-PLYP improves for a wide range of chemical systems emphasizes the need of (virtual) orbital-dependent terms that describe nonlocal electron correlation in accurate exchange-correlation functionals. From a practical point of view, the new functional seems to be very robust and it is thus suggested as an efficient quantum chemical method of general purpose.

Geometries and Properties of Excited States in the Gas Phase and in Solution: Theory and Application of a Time-dependent Density Functional Theory Polarizable Continuum Model

Article

Full-text available

Apr 2006

In this paper we present the theory and implementation of analytic derivatives of time-dependent density functional theory (TDDFT) excited states energies, both in vacuo and including solvent effects by means of the polarizable continuum model. The method is applied to two case studies: p-nitroaniline and 4-(dimethyl)aminobenzonitrile. For both molecules PCM-TDDFT is shown to be successful in supporting the analysis of experimental data with useful insights for a better understanding of photophysical and photochemical pathways in solution.

Introduction to Magnetochemistry

Article

Jan 1968

A. Earnshaw

Phys. Rev. Lett

Article

Jan 1996

Biological activity of Co(III) and Ni(II) complexes of pyridine-2-carbaldehyde N(4)-methylthiosemicarbazone: Synthesis, characterization, crystal structure of Co(III) complex of pyridine-2-carbaldehyde N(4)-methylthiosemicarbazone1

Article

Jul 2012

Transition metal complexes formulated as [Co(L)2]ClO4 (I) and [Ni(L)2] · H2O (II), where HL = pyridine-2-carbaldehyde N(4)-methylthiosemicarbazone, have been synthesized. Complex I was characterized by elemental analysis, IR, MS and single-crystal X-ray diffraction studies. In complex I, the ligand is N2S tridentate, coordinating to the metal center through pyridine nitrogen, imine nitrogen and sulfur atoms. Hydrogen bonds link the different components to stabilize the crystal structure. Preliminary in vitro screening indicated that the free ligand was active against various bacteria and fungi and all the tested compounds showed significant antitumor activity against K562 leukaemia cell line, and can therefore be candidates for further stages of screening in vitro and/or in vivo.

Synthesis, crystal structures and biological activities of 2-acetylpyridine N(4)-cyclohexylthiosemicarbazone and its manganese(II) and nickel(II) complexes

Article

Dec 2010
INORG CHEM COMMUN

2-Acetylpyridine N(4)-cyclohexylthiosemicarbazone (HL) and its manganese(II) and nickel(II) complexes formulated as [Mn(L)2] (1) and [Ni(L)2] (2) have been synthesized and characterized by elemental analysis, infrared spectra, mass spectra, and single-crystal X-ray diffraction studies. In the two complexes, the coordination polyhedron approaches an octahedron, where the two ligands coordinate to the metal via the pyridine nitrogen atom and the nitrogen and sulfur donors of the thiosemicarbazide moiety. Biological studies, carried out in vitro against selected bacteria and K562 leukaemia cell line, respectively, have shown that the free ligand and its complexes exhibited distinct differences in the biological activities.

SHELXS-97, Program for crystal structure solution

Article

Jan 1990

M. Sheldrick

Manganese(II) complexes with N 4-methyl-4-nitrobenzaldehyde, N 4-methyl-4-nitroacetofenone, and N 4-methyl-4-nitrobenzophenone thiosemicarbazone: Investigation of in vitro activity against Trypanosoma cruzi

Article

Jul 2010
POLYHEDRON

Thiosemicarbazones are known to be active against different pathogenic microorganisms including Trypanosoma cruzi, the etiological agent of Chagas disease. In the search for new therapeutic drugs against this illness, the complexes [Mn(H4NO2Fo4M)2Cl2] (1), [Mn(H4NO2Ac4M)2Cl2] (2) and [Mn(H4NO2Bz4M)2Cl2] (3) of N4-methyl-4-nitrobenzaldehyde thiosemicarbazone (H4NO2Fo4M), N4-methyl-4-nitroacetophenone thiosemicarbazone (H4NO2Ac4M) and N4-methyl-4-nitrobenzophenone thiosemicarbazone (H4NO2Bz4M) were obtained and screened in vitro against bloodstream and intracellular forms of T. cruzi. H4NO2Fo4M, H4NO2Ac4M and their Mn(II) complexes displayed poor effect on bloodstream trypomastigotes, with IC50 values ranging from 68 to >200μM. However, although H4NO2Bz4M was also not active, its corresponding Mn(II) complex presented high effect on this T. cruzi form, with an IC50 value of 19μM. The effect of complex (3), against trypomastigotes of T. cruzi supports further in vitro as well as in vivo studies.

First novel anti-tuberculosis drug in 40 years

Article

Feb 2013
NAT BIOTECHNOL

Randy Osborne

An efficient implementation of time-dependent density-functional theory for the calculation of excitation energies of large molecules

Article

Nov 1998

Time-dependent density-functional (TDDFT) methods are applied within the adiabatic approximation to a series of molecules including C70. Our implementation provides an efficient approach for treating frequency-dependent response properties and electronic excitation spectra of large molecules. We also present a new algorithm for the diagonalization of large non-Hermitian matrices which is needed for hybrid functionals and is also faster than the widely used Davidson algorithm when employed for the Hermitian case appearing in excited energy calculations. Results for a few selected molecules using local, gradient-corrected, and hybrid functionals are discussed. We find that for molecules with low lying excited states TDDFT constitutes a considerable improvement over Hartree–Fock based methods (like the random phase approximation) which require comparable computational effort. © 1998 American Institute of Physics.

Energy–Adjusted Ab Initio Speudopotentials for the First Row Transition Elements

Article

Jan 1987

Nonrelativistic and quasirelativistic ab‐initio pseudopotentials representing the Ne‐like X(Z−10)+ cores (X=Sc–Zn) of the first row transition metals and optimized (8s7p6d1f )/[6s5p3d1f ]‐GTO valence basis sets for use in molecular calculations have been generated. Excitation and ionization energies of the low lying states of Sc through Zn from numerical HF‐ as well as SCF‐ and CI(SD)‐pseudopotential calculations using the derived basis sets differ by less than 0.1 eV from corresponding all‐electron results.

Molecular excitation energies to high-lying bound states from time-dependent density-functional response theory: Characterization and correction of the time-dependent local density approximation ionization threshold

Article

Mar 1998

This paper presents an evaluation of the performance of time-dependent density-functional response theory (TD-DFRT) for the calculation of high-lying bound electronic excitation energies of molecules. TD-DFRT excitation energies are reported for a large number of states for each of four molecules: N2, CO, CH2O, and C2H4. In contrast to the good results obtained for low-lying states within the time-dependent local density approximation (TDLDA), there is a marked deterioration of the results for high-lying bound states. This is manifested as a collapse of the states above the TDLDA ionization threshold, which is at −ϵHOMOLDA (the negative of the highest occupied molecular orbital energy in the LDA). The −ϵHOMOLDA is much lower than the true ionization potential because the LDA exchange-correlation potential has the wrong asymptotic behavior. For this reason, the excitation energies were also calculated using the asymptotically correct potential of van Leeuwen and Baerends (LB94) in the self-consistent field step. This was found to correct the collapse of the high-lying states that was observed with the LDA. Nevertheless, further improvement of the functional is desirable. For low-lying states the asymptotic behavior of the exchange-correlation potential is not critical and the LDA potential does remarkably well. We propose criteria delineating for which states the TDLDA can be expected to be used without serious impact from the incorrect asymptotic behavior of the LDA potential. © 1998 American Institute of Physics.

Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals

Article

Jan 1985

Ab initio effective core potentials (ECP’s) have been generated to replace the innermost core electron for third‐row (K–Au), fourth‐row (Rb–Ag), and fifth‐row (Cs–Au) atoms. The outermost core orbitals—corresponding to the ns2np6 configuration for the three rows here—are not replaced by the ECP but are treated on an equal footing with the nd, (n+1)s and (n+1)p valence orbitals. These ECP’s have been derived for use in molecular calculations where these outer core orbitals need to be treated explicitly rather than to be replaced by an ECP. The ECP’s for the forth and fifth rows also incorporate the mass–velocity and Darwin relativistic effects into the potentials. Analytic fits to the potentials are presented for use in multicenter integral evaluation. Gaussian orbital valence basis sets are developed for the (3s, 3p, 3d, 4s, 4p), (4s, 4p, 4d, 5s, 5p), and (5s, 5p, 5d, 6s, 6p) ortibals of the three respective rows.

Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients

Article

Feb 2013
CLIN EXP IMMUNOL

Synthesis and Crystal Structure of a Series of Transition Metal Complexes with Sulfur‐Containing Ligands

Article

Aug 2006

A series of transition metal complexes [Mn(HL)2](ClO4)2 · 0.25H2O (1), [Fe(L)2](ClO4) · H2O (2), [Fe(L)2](BF4) · C7H8N4 (3), [Co(HL)(L)](ClO4) · H2O (4), [Co(HL)(L)](ClO4) · 1.5C2H5OH (5), and [Ni(L)2] · H2O (6), where HL=2‐acetylpyridine thiosemicarbazone, C7H8N4=bis(pyrazolyl)methane, have been synthesized and their structures were determined. All the metal centers are six‐coordinate with 4 nitrogen atoms and 2 sulfur atoms from 2 ligands. Complexes 1–3 and 5 are mononuclear complexes while complexes 4 and 6 contain hydrogen bonds that separately connect the molecule units into multi‐dimensional structure and aggregation. These complexes are potential molecular bricks of the multi‐dimensional or heterometallic complexes containing sulfur atoms.

Activity on Trypanosoma cruzi, erythrocytes lysis and biologically relevant physicochemical properties of Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones

Article

Sep 2012

The Requirement for Manganese and Oxygen in the Isoniazid-Dependent Inactivation of Mycobacterium tuberculosis Enoyl Reductase

Article

Mar 1997

Synthesis, crystal structure, electrochemical, and spectroelectrochemical properties of the new manganese(III) complex [MnIII(BBPEN)][PF6] [H2BBPEN = N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-methylpyridyl)ethylenediamine]

Article

Nov 1992

Two new hexadentate ligands (H2L) derived from alkyldiamines containing phenolate-type and alpha-pyridyl pendant arms have been prepared: N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-methylpyridyl)ethylenediamine (H2BBPEN; C28H30N4O2) and N,N'-bis(2-hydroxybenzyl)-N'-bis(2-methylpyridyl)-1,3-propanediamine (H2BBPPN; C29H32N4O2). The reaction of H2L with Mn(CH3COO)3.2H2O in methanolic solution affords upon addition of NH4PF6 monomeric Mn(III) complexes ([MnL][PF6]) in high yields. The crystal structure of [Mn(BBPEN)][PF6] (1) has been determined by X-ray crystallography. Crystal data: monoclinic, space group P2(1)/n, a = 11.310 (2) angstrom, b = 21.266 (3) angstrom, c = 11.791 (4) angstrom, beta = 106.7 (2)-degrees, V = 2716 (1) angstrom3, Z = 4. The structure has been refined to an R factor of 6.3% based on 3023 observed reflections. In the complex cation of 1, the manganese is coordinated by the hexadentate BBPEN2- ligand producing a distorted octahedral MnN4O2 geometry, with two pyridyl groups, bound in the trans position. Average Mn-O and Mn-N (two types) bond lengths are 1.867 (4), 2.101 (4), and 2.244 (5) angstrom. The presence of four short Mn-O and Mn-N bonds and two long Mn-N bonds are consistent with Jahn-Teller effects. The magnetic moments (4.85-4.90 mu(B)) of the [MnL] [PF6] complexes correspond to the d4 configuration. Cyclic voltammograms of (1) and [Mn(BBPPN)] [PF6] (2) in acetonitrile show two quasi-reversible one-electron-transfer processes corresponding to Mn(IV)/Mn(III) at 0.49 and 0.61 V and Mn(III)/Mn(II) at -0.37 and -0.44 V vs. Fc+/Fc. Spectroelectrochemistry in the UV-vis spectral region has been used to characterize the Mn(IV) analogous of these complexes. E-degrees' values obtained from these spectropotentiostatic data are consistent with values determined from cyclic voltammograms. The electronic spectra of the oxidized species show two intense LMCT transitions in the 400-800-nm range, and solutions of [Mn(IV)(BBPEN)]2+ are stable for at least 24 h under argon. The X-band EPR spectra of this solution obtained at 110 K shows prominent features at g1 = 5.84, g2 = 4.77, and g3 = 1.99 and is consistent with a rhombically distorted S = 3/2 spin system.

Revised Basis Sets for the LANL Effective Core Potentials

Article

Jun 2008

We suggest a new contraction of the basis sets associated with the Hay-Wadt relativistic effective core potentials (RECPs) for the main group and transition metal atoms. These bases are more suitable for density functional theory investigations than the previous ‘double-ζ’ contractions based upon Hartree−Fock atomic results. The original Hay-Wadt primitives are now contracted [5s5p3d], [4s4p3d], and [4s4p3d] for the first, second, and third transition series, respectively, and denoted as LANL2TZ basis sets. For the main group atoms, we advocate using a completely uncontracted basis denoted LANL08. While modestly extending the size of the basis, the resulting sets should be suitable for both DFT and wave function based approaches. The valence bases for the transition metal atoms can be supplemented with the polarization functions determined by Frenking.

SHELXTI93, Program for crystal structure refinement

Book

Jan 1997

G M Sheldrick

Molecular mechanism of rifampicin and isoniazid resistance in Mycobacterium tuberculosis from Bangladesh

Article

Aug 2012

Despite having 100% coverage of directly observed treatment short-course, multi drug-resistant (MDR) tuberculosis (TB) is still increasing in Bangladesh. Early detection of MDR-TB by rapid molecular test and early initiation of treatment will effectively stop this trend. To develop rapid diagnostic tools, molecular characterization of genes conferring Mycobacterium tuberculosis resistance to rifampicin (RIF) and isoniazid (INH) will be required. Hence, this study elucidated the molecular mechanism RIF and INH resistance in 218 MDR strains from hospitalized (n = 161) and non-hospitalized (n = 57) TB patients in Bangladesh. Mutations in rpoB gene were detected in 207 (95.0%) with majority at codon 531 (52.3%). Mutations in katG or inhA or both were detected in 206 (94.5%) with majority at codon 315 of katG (83.9%). It was noteworthy that a novel C to T mutation at position -34 and G to A mutations at position -47 in inhA regulatory region were found, respectively, in combination with mutation at codon 315 of katG. This is the first comprehensive molecular analysis of rpoB and katG genes and inhA regulatory regions of MDR isolates from Bangladesh. This study provides basic data for the construction of low cost tailor-made molecular system for rapid diagnosis of MDR-TB in Bangladesh.

Synthesis, spectral characterization and crystal structure of 2-benzoylpyridine N(4)-cyclohexylthiosemicarbazone

Article

Nov 2004
J MOL STRUCT

The synthesis, characterization, molecular and crystal structure of 2-benzoylpyridine N(4)-cyclohexylthiosemicarbazone is reported. IR analysis was done and NMR assignments using COSY homonuclear and HMQC heteronuclear correlation techniques were carried out. The electronic structure of the compound was revealed by solid state reflectance studies and in chloroform solution. The infrared spectrum gives evidence for the compound in the thione form, which is consistent with the observed bond lengths from the crystal structure. The compound crystallizes into a monoclinic lattice with space group P21/n. The non-coplanarity of the two benzene rings in the compound is confirmed from the dihedral angles. Puckering analysis and least square planes calculations point out to chair conformation of the cyclohexyl ring.

Geometric derivatives of excitation energies using SCF and DFT

Article

Jul 1999
CHEM PHYS LETT

There is increasing interest in using the methods of time-dependent density functional theory to calculate electronic excitation energies. We have implemented an analytic gradient method to find the geometric derivatives of the excitation energies. When added to the gradient for the ground state, this yields the excited-state energy derivatives. This enables the efficient generation and searching of excited-state potential energy surfaces to obtain excited-state geometries and other properties. The initial implementation is for SCF methods and for the local density approximation. Some examples of excited-state geometry optimizations are given.

Multifrequency electron paramagnetic resonance and theoretical studies of a Mn(II) (S=5/2) complex: The role of geometrical elements on the Zero Field Splitting parameters

Article

Oct 2009
POLYHEDRON

The Zero Field Splitting (ZFS) parameters of the mononuclear Mn(II) (S=5/2) compound [Mn(Ac4Ph)2], where HAc4Ph stands for 4-phenyl-2-acetylpyridine thiosemicarbazone, are determined by dual mode X-band and high field/high frequency electron paramagnetic resonance spectroscopy. Density functional theory (DFT) calculations reproduce both the sign and absolute value of the axial parameter D of the ZFS tensor, whose distribution is quantitatively correlated to distribution on geometrical elements of the complex.

N-4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action

Article

Apr 2012

N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.

Vanadium complexes with thiosemicarbazones: Synthesis, characterization, crystal structures and anti-Mycobacterium tuberculosis activity

Article

Feb 2009
POLYHEDRON

The development of more efficient anti-tuberculosis drugs is of interest. Three oxovanadium(IV) and three cis-dioxovanadium(V) complexes with thiosemicarbazone derivatives bearing moieties with different lipophilicity have been prepared and had their inhibitory activity against Mycobacterium tuberculosis H(37)Rv ATCC 27294 evaluated. The analytical methods used by the complexes' characterization included IR, EPR, (1)H, (13)C and (51)V NMR spectroscopies, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. [VO(acac)(aptsc)], [VO(acac)(apmtsc)] and [VO(acac)(apptsc)] (acac = acetylacetonate; Haptsc = 2-acetylpyridinethiosemicarbazone; Hapmtsc = 2-acetylpyridine-N(4)-methyl-thiosemicarbazone and Happtsc = 2-acetylpyridine-N(4)-phenyl-thiosemicarbazone) are paramagnetic and their EPR spectra are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral structures of rhombic symmetry and with the oxidation state +IV for the vanadium atom. As result of oxidation of the vanadium(IV) complexes above, the diamagnetic cis-dioxovanadium(V) complexes [VO(2)(aptsc)[, [VO(2)(apmtsc)[ and [VO(2)(apptsc)] are formed. Their (1)H, (13)C and (51)V NMR spectra were acquired and support a distorted square pyramidal geometry for them, in accord with the solid state X-ray structures determined for [VO(2)(aptsc)] and [VO(2)(apmtsc)]. In general, the vanadium compounds show comparable or larger anti-M. tuberculosis activities than the free thiosemicarbazone ligands, with MIC values within 62.5-1.56 (mu g/mL). (C) 2008 Elsevier Ltd. All rights reserved.

Neutral Gold Complexes with Tridentate SNS Thiosemicarbazide Ligands

Article

Feb 2012
INORG CHEM

Na[AuCl(4)]·2H(2)O reacts with tridentate thiosemicarbazide ligands, H(2)L1, derived from N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chloride and thiosemicarbazides under formation of air-stable, green [AuCl(L1)] complexes. The organic ligands coordinate in a planar SNS coordination mode. Small amounts of gold(I) complexes of the composition [AuCl(L3)] are formed as side-products, where L3 is an S-bonded 5-diethylamino-3-phenyl-1-thiocarbamoyl-1,2,4-triazole. The formation of the triazole L3 can be explained by the oxidation of H(2)L1 to an intermediate thiatriazine L2 by Au(3+), followed by a desulfurization reaction with ring contraction. The chloro ligands in the [AuCl(L1)] complexes can readily be replaced by other monoanionic ligands such as SCN(-) or CN(-) giving [Au(SCN)(L1)] or [Au(CN)(L1)] complexes. The complexes described in this paper represent the first examples of fully characterized neutral Gold(III) thiosemicarbazone complexes. All the [AuCl(L1)] compounds present a remarkable cell growth inhibition against human MCF-7 breast cancer cells. However, systematic variation of the alkyl groups in the N(4)-position of the thiosemicarbazone building blocks as well as the replacement of the chloride by thiocyanate ligands do not considerably influence the biological activity. On the other hand, the reduction of Au(III) to Au(I) leads to a considerable decrease of the cytotoxicity.

Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy

Article

Oct 2005

Gaussian basis sets of quadruple zeta valence quality for Rb-Rn are presented, as well as bases of split valence and triple zeta valence quality for H-Rn. The latter were obtained by (partly) modifying bases developed previously. A large set of more than 300 molecules representing (nearly) all elements-except lanthanides-in their common oxidation states was used to assess the quality of the bases all across the periodic table. Quantities investigated were atomization energies, dipole moments and structure parameters for Hartree-Fock, density functional theory and correlated methods, for which we had chosen Møller-Plesset perturbation theory as an example. Finally recommendations are given which type of basis set is used best for a certain level of theory and a desired quality of results.

Adiabatic time-dependent density functional methods for excited state properties

Article

Oct 2002

This work presents theory, implementation, and validation of excited state properties obtained from time-dependent density functional theory (TDDFT). Based on a fully variational expression for the excited state energy, a compact derivation of first order properties is given. We report an implementation of analytic excited state gradients and charge moments for local, gradient corrected, and hybrid functionals, as well as for the configuration interaction singles (CIS) and time-dependent Hartree-Fock (TDHF) methods. By exploiting analogies to ground state energy and gradient calculations, efficient techniques can be transferred to excited state methods. Benchmark results demonstrate that, for low-lying excited states, geometry optimizations are not substantially more expensive than for the ground state, independent of the molecular size. We assess the quality of calculated adiabatic excitation energies, structures, dipole moments, and vibrational frequencies by comparison with accurate experimental data for a variety of excited states and molecules. Similar trends are observed for adiabatic excitation energies as for vertical ones. TDDFT is more robust than CIS and TDHF, in particular, for geometries differing significantly from the ground state minimum. The TDDFT excited state structures, dipole moments, and vibrational frequencies are of a remarkably high quality, which is comparable to that obtained in ground state density functional calculations. Thus, yielding considerably more accurate results at similar computational cost, TDDFT rivals CIS as a standard method for calculating excited state properties in larger molecules. (C) 2002 American Institute of Physics.

Stabilizing High-Valent Metal Ions with a Ketimide Ligand Set: Synthesis of Mn(N═C t Bu 2 ) 4

Article

May 2011
INORG CHEM

Reaction of MnCl(2) with 4 equiv of Li(N=C(t)Bu(2)) generates [Li(THF)](2)[Mn(N=C(t)Bu(2))(4)] (1) in 80% yield. Oxidation of 1 with 0.5 equiv of I(2) produces [Li][Mn(N=C(t)Bu(2))(4)] (2) in 88% yield. Both complexes 1 and 2 exhibit tetrahedral structures about the Mn center in the solid-state, as determined by X-ray crystallography. Reaction of 2 with 12-crown-4 generates [Li(12-crown-4)(2)][Mn(N=C(t)Bu(2))(4)] (3) in 94% yield. Interestingly, in the solid-state, complex 3 exhibits a squashed tetrahedral structure about Mn. Addition of 1 equiv of I(2) to 1 generates the Mn(IV) ketimide, Mn(N=C(t)Bu(2))(4) (4), in 75% yield. Complex 4 was fully characterized, including analysis by X-ray crystallography and cyclic voltammetry. Like 3, complex 4 also exhibits a squashed tetrahedral structure in the solid-state. Interestingly, thermolysis of complex 4 at 50 °C for 6 h results in the formation of Mn(3)(N=C(t)Bu(2))(6) (6), which can be isolated in 49% yield. Also observed in the reaction mixture is pivalonitrile, isobutylene, and isobutene, the products of ketimide ligand oxidation. We have also synthesized the homoleptic Cr(IV) ketimide complex, Cr(N=C(t)Bu(2))(4) (5), and have analyzed its electrochemical properties with cyclic voltammetry.

Antimycobacterial and antitumor activities of Palladium(II) complexes containing isonicotinamide (isn): X-ray structure of trans-[Pd(N-3)(2)(isn)(2)]

Article

Nov 2010

Complexes of the type trans-[PdX(2)(isn)(2)] {X = Cl (1), N(3) (2), SCN (3), NCO (4); isn = isonicotinamide} were synthesized and evaluated for in vitro antimycobacterial and antitumor activities. The coordination mode of the isonicotinamide and the pseudohalide ligands was inferred by IR spectroscopy. Single crystal X-ray diffraction determination on 2 showed that coordination geometry around Pd(II) is nearly square planar, with the ligands in a trans configuration. All the compounds demonstrated better in vitro activity against Mycobacterium tuberculosis than isonicotinamide and pyrazinamide. Among the complexes, compound 2 was found to be the most active with MIC of 35.89 μM. Complexes 1-4 were also screened for their in vitro antitumor activity towards LM3 and LP07 murine cancer cell lines.

Mn(II), Co(II) and Zn(II) complexes with heterocyclic substituted thiosemicarbazones: Synthesis, characterization, X-ray crystal structures and antitumor comparison

Article

Jul 2010

Transition metal complexes Mn(L(1))(2) (1), Mn(L(2))(2) (2), Co(L(3))(2)Cl 4H(2)O (3), Zn(L(3))(2) DMF (4), Co(HL(4))(2)(ClO(4))(2) 3H(2)O (5) and Zn(L(5))(2) DMF (6) where HL(1)=2-acetylpyridine thiosemicarbazone, HL(2)=2-acetylpyridine N(4)-methylthiosemicarbazone, HL(3)=2-benzoylpyridine thiosemicarbazone, HL(4)=2-benzoylpyridine N(4)-methylthiosemicarbazone and HL(5)=2-benzoylpyridine N(4)-phenylthiosemicarbazone, have been synthesized. The complexes 1, 2, 5 and 6 were characterized by elemental analysis, IR spectra and single-crystal X-ray diffraction studies. Preliminary in vitro screening indicated that all the tested compounds showed significant antitumor activity against K562 leucocythemia cancer cell line.

Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: Anti-Mycobacterium tuberculosis activity and cytotoxicity

Article

May 2010

The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of "first line" or "second line" drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates.

Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-D-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC)

Article

Nov 2009

High-throughput screening of 201,368 compounds revealed that 1-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)-1H-benzo[d]imidazol-2(3H)-one (SID 7975595) inhibited RmlC a TB cell wall biosynthetic enzyme. SID 7975595 acts as a competitive inhibitor of the enzyme's substrate and inhibits RmlC as a fast-on rate, fully reversible inhibitor. An analog of SID 7975595 had a K(i) of 62nM. Computer modeling showed that the binding of the tethered two-ringed system into the active site occurred at the thymidine binding region for one ring system and the sugar region for the other ring system.

2-Acetylpyridine Thiosemicarbazones are Potent Iron Chelators and Antiproliferative Agents: Redox Activity, Iron Complexation and Characterization of their Antitumor Activity

Article

Mar 2009
J MED CHEM

Through systematic structure-activity studies of the 2-benzoylpyridine thiosemicarbazone (HBpT), 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (HNBpT) and dipyridylketone thiosemicarbazone (HDpT) series of iron (Fe) chelators, we identified structural features necessary to form Fe complexes with potent anticancer activity (J. Med. Chem. 2007, 50, 3716-3729). In this investigation, we generated the related 2-acetylpyridine thiosemicarbazone (HApT) analogues to examine the influence of the methyl group at the imine carbon. Four of the six HApT chelators had potent antitumor activity (IC(50): 0.001-0.002 microM) and Fe chelation efficacy that was similar to the most effective HBpT and HDpT ligands. The HApT Fe complexes had the lowest Fe(III/II) redox potentials of any thiosemicarbazone series we have generated. This property, in combination with their ability to effectively chelate cellular Fe, make the HApT series one of the most potent antiproliferative agents developed by our group.

Characterizations of Chloro and Aqua Mn(II) Mononuclear Complexes with Amino-Pyridine Ligands. Comparison of Their Electrochemical Properties With Those of Fe(II) Counterparts

Article

Dec 2008
INORG CHEM

The solution behavior of mononuclear Mn(II) complexes, namely, [(L(5)(2))MnCl](+) (1), [(L(5)(3))MnCl](+) (2), [(L(5)(2))Mn(OH(2))](2+) (3), [(L(5)(3))Mn(OH(2))](2+) (4), and [(L(6)(2))Mn(OH(2))](2+) (6), with L(5)(2/3) and L(6)(2) being penta- and hexadentate amino-pyridine ligands, is investigated in MeCN using EPR, UV-vis spectroscopies, and electrochemistry. The addition of one chloride ion onto species 6 leads to the formation of the complex [(L(6)(2))MnCl](+) (5) that is X-ray characterized. EPR and UV-vis spectra indicate that structure and redox states of complexes 1-6 are maintained in MeCN solution. Chloro complexes 1, 2, and 5 show reversible Mn(II)/Mn(III) process at 0.95, 1.02, and 1.05 V vs SCE, respectively, whereas solvated complexes 3, 4, and 6 show an irreversible anodic peak around 1.5 V vs SCE. Electrochemical oxidations of 1 and 5 leading to the Mn(III) complexes [(L(5)(2))MnCl](2+) (7) and [(L(6)(2))MnCl](2+) (8) are successful. The UV-vis signatures of 7 and 8 show features associated with chloro to Mn(III) LMCT and d-d transitions. The X-ray characterization of the heptacoordinated Mn(III) species 8 is also reported. The analogous electrochemical generation of the corresponding Mn(III) complex was not possible when starting from 2. The new mixed-valence di-mu-oxo [(L(5)(2))Mn(muO)(2)Mn(L(5)(2))](3+) species (9) can be obtained from 3, whereas the sister [(L(5)(3))Mn(muO)(2)Mn(L(5)(3))](3+) species can not be generated from 4. Such different responses upon oxidations are commented on with the help of comparison with related Mn/Fe complexes and are discussed in relation with the size of the metallacycle formed between the diamino bridge and the metal center (5- vs 6-membered). Lastly, a comparison between redox potentials of the studied Mn(II) complexes with those of Fe(II) analogues is drawn and completed with previously reported data on Mn/Fe isostructural systems. This gives us the opportunity to get some indirect insights into the metal specificity encountered in enzymes among which superoxide dismutase is the archetypal model.

Density-functional approximation for the correlation energy of the inhomogeneous electron gas

Article

Jul 1986
Phys Rev B

John P. Perdew

Langreth and Mehl (LM) and co-workers have developed a useful spin-density functional for the correlation energy of an electronic system. Here the LM functional is improved in two ways: (1) The natural separation between exchange and correlation is made, so that the density-gradient expansion of each is recovered in the slowly varying limit. (2) Uniform-gas and inhomogeneity effects beyond the randomphase approximation are built in. Numerical results for atoms, positive ions, and surfaces are close to the exact correlation energies, with major improvements over the original LM approximation for the ions and surfaces.

Generalized Gradient Approximation Made Simple

Article

Nov 1996
PHYS REV LETT

Generalized gradient approximations (GGA{close_quote}s) for the exchange-correlation energy improve upon the local spin density (LSD) description of atoms, molecules, and solids. We present a simple derivation of a simple GGA, in which all parameters (other than those in LSD) are fundamental constants. Only general features of the detailed construction underlying the Perdew-Wang 1991 (PW91) GGA are invoked. Improvements over PW91 include an accurate description of the linear response of the uniform electron gas, correct behavior under uniform scaling, and a smoother potential. {copyright} {ital 1996 The American Physical Society.}

Search for New Drugs for Treatment of Tuberculosis

Article

Aug 2001

Ian M. Orme

Single-Molecule Magnets: Structural Characterization, Magnetic Properties, and 19 F NMR Spectroscopy of a Mn 12 Family Spanning Three Oxidation Levels

Article

Aug 2005

The syntheses, crystal structures, and magnetic properties of [Mn(12)O(12)(O(2)CC(6)F(5))(16)(H(2)O)(4)] (2), (NMe(4))[Mn(12)O(12)(O(2)CC(6)F(5))(16)(H(2)O)(4)] (3), and (NMe(4))(2)[Mn(12)O(12)(O(2)CC(6)F(5))(16)(H(2)O)(4)] (4) are reported. Complex 2 displays quasi-reversible redox couples when examined by cyclic voltammetry in CH(2)Cl(2): one-electron reductions are observed at 0.64 and 0.30 V vs ferrocene. The reaction of complex 2 with 1 and 2 equiv of NMe(4)I yields the one- and two-electron reduced analogues, 3 and 4, respectively. Complexes 2.3CH(2)Cl(2), 3.4.5CH(2)Cl(2).(1)/(2)H(2)O, and 4.6C(7)H(8) crystallize in the triclinic P, monoclinic P2/c, and monoclinic C2/c space groups, respectively. The molecular structures are all very similar, consisting of a central [Mn(IV)O(4)] cubane surrounded by a nonplanar alternating ring of eight Mn and eight mu(3)-O(2)(-) ions. Peripheral ligation is provided by 16 bridging C(6)F(5)CO(2)(-) and 4 H(2)O ligands. Bond valence sum calculations establish that the added electrons in 3 and 4 are localized on former Mn(III) ions giving trapped-valence Mn(IV)(4)Mn(III)(7)Mn(II) and Mn(IV)(4)Mn(III)(6)Mn(II)(2) anions, respectively. (19)F NMR spectroscopy in CD(2)Cl(2) shows retention of the solid-state structure upon dissolution and detrapping of the added electrons in 3 and 4 among the outer ring of Mn ions on the (19)F NMR time scale. DC studies on dried microcrystalline samples of 2, 3, and 4.2.5C(7)H(8) restrained in eicosane in the 1.80-10.0 K and 1-70 kG ranges were fit to give S = 10, D = -0.40 cm(-)(1), g = 1.87, D/g = 0.21 cm(-)(1) for 2, S = 19/2, D = -0.34 cm(-)(1), g = 2.04, D/g = 0.17 cm(-)(1) for 3, and S = 10, D = -0.29 cm(-)(1), g = 2.05, D/g = 0.14 cm(-)(1) for 4, where D is the axial zero-field splitting parameter. The clusters exhibit out-of-phase AC susceptibility signals (chi(M)' ') indicative of slow magnetization relaxation in the 6-8 K range for 2, 4-6 K range for 3, and 2-4 K range for 4; the shift to lower temperatures reflects the decreasing magnetic anisotropy upon successive reduction and, hence, the decreasing energy barrier to magnetization relaxation. Relaxation rate vs T data obtained from chi(M)' ' vs AC oscillation frequency studies down to 1.8 K were combined with rate vs T data from DC magnetization decay vs time measurements at lower temperatures to generate an Arrhenius plot from which the effective barrier (U(eff)) to magnetization reversal was obtained; the U(eff) values are 59 K for 2, 49 and 21 K for the slower- and faster-relaxing species of 3, respectively, and 25 K for 4. Hysteresis loops obtained from single-crystal magnetization vs DC field scans are typical of single-molecule magnets with the coercivities increasing with decreasing T and increasing field sweep rate and containing steps caused by the quantum tunneling of magnetization (QTM). The step separations gave D/g values of 0.22 cm(-)(1) for 2, 0.15 and 0.042 cm(-)(1) for the slower- and faster-relaxing species of 3, and 0.15 cm(-)(1) for 4.

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Abstract

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